Secreted human proteins

ABSTRACT

Fifteen secreted human proteins and full-length cDNA sequences encoding the proteins have been identified. The proteins have various potential uses as therapeutics, such as for stimulating blood cell generation in patients receiving cancer chemotherapy, for treatment of bone marrow transplantation patients, and for healing fractured bones. The proteins and cDNA sequences can also be used, inter alia, for targeting other proteins to the membrane or extracellular milieu.

TECHNICAL AREA OF THE INVENTION

[0001] This invention relates to proteins secreted from bone marrow and from fetal liver, and to polynucleotides encoding the secreted proteins. The invention also relates to therapeutic and diagnostic utilities for the polynucleotides and proteins.

BACKGROUND OF THE INVENTION

[0002] Human tissues, such as fetal liver and bone marrow stromal cells, secrete a variety of protein factors. Some of these factors are required for the formation of blood and bone cells and for other physiological processes. Regulatory factors which are known to be involved in hematopoiesis and/or bone development include SCF, IL-3, IL-6, GM-CSF, M-CSF, EPO, TPO, bone morphogenic proteins, erythroid potentiating factor, and TGF-β. However, it is believed that additional secreted protein factors which control hematopoiesis and bone morphogenesis remain to be identified. Other secreted proteins may play a role in cell-cell interaction and regulation of cell growth, both of which are related to cancer. There is a need to identify such proteins.

SUMMARY OF THE INVENTION

[0003] It is an object of the invention to provide novel secreted proteins and polynucleotide sequences which encode the proteins. These and other objects of the invention are provided by one or more of the embodiments described below.

[0004] One embodiment of the invention is an isolated and purified protein having an amino acid sequence which is at least 85% identical to an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30. Percent identity can be determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1.

[0005] Another embodiment of the invention is an isolated and purified polypeptide comprising at least 8 contiguous amino acids of an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30.

[0006] Still another embodiment of the invention is a fusion protein comprising a first protein segment and a second protein segment fused together by means of a peptide bond. The first protein segment consists of at least 8 contiguous amino acids of an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30.

[0007] Yet another embodiment of the invention is a preparation of antibodies which specifically bind to a protein having an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30.

[0008] Even another embodiment of the invention is a cDNA molecule which encodes a protein having an amino acid sequence which is at least 85% identical to an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30. Percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1.

[0009] A further embodiment of the invention is a cDNA molecule which encodes at least 8 contiguous amino acids of an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30.

[0010] Another embodiment of the invention is a cDNA molecule comprising a nucleotide sequence selected from the group consisting of at least 69 contiguous nucleotides of SEQ ID NO:1, at least 550 contiguous nucleotides of SEQ ID NO:3, at least 180 contiguous nucleotides of SEQ ID NO:5; at least 27 contiguous nucleotides of SEQ ID NO:7, and at least 11 contiguous nucleotides of SEQ ID NO:9.

[0011] Still another embodiment of the invention is a cDNA molecule which is at least 85% identical to a nucleotide sequence selected from the group consisting of the nucleotide sequences shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29. Percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1.

[0012] Even another embodiment of the invention is an isolated and purified polynucleotide molecule comprising a nucleotide sequence which hybridizes to a nucleotide sequence selected from the group consisting of the nucleotide sequences shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29 after washing with 0.2× SSC at 65° C. The nucleotide sequence encodes a protein having an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30.

[0013] Yet another embodiment of the invention is a polynucleotide construct comprising a promoter and a polynucleotide segment encoding at least 8 contiguous amino acids of a protein as shown in SEQ ID NOS:2, 4, 6, 8, or 10. The polynucleotide segment is located downstream from the promoter. Transcription of the polynucleotide segment initiates at the promoter.

[0014] A further embodiment of the invention is a host cell comprising a polynucleotide construct. The polynucleotide construct comprises a promoter and a polynucleotide segment encoding at least 8 contiguous amino acids of a protein as shown in SEQ ID NOS:2, 4, 6, 8, or 10. The polynucleotide segment is located downstream from the promoter. Transcription of the polynucleotide segment initiates at the promoter.

[0015] Even another embodiment of the invention is a method of producing a human protein. A host cell comprising a polynucleotide construct is cultured in a culture medium. The polynucleotide construct comprises a promoter and a polynucleotide segment encoding at least 8 contiguous amino acids of a protein as shown in SEQ ID NOS:2, 4, 6, 8, or 10. The polynucleotide segment is located downstream from the promoter. Transcription of the polynucleotide segment initiates at the promoter. The human protein is purified from the cell or the culture medium.

[0016] The present invention thus provides the art with the amino acid sequences of fifteen full-length novel human secreted proteins and with polynucleotide molecules which encode these proteins. The invention can be used to, inter alia, to produce secreted proteins for therapeutic and diagnostic purposes.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Fifteen cDNA clones have been identified which encode novel human secreted proteins. One cDNA clone (ch1268) contains a 1313 basepair insert (SEQ ID NO:1) that encodes a polypeptide of 325 amino acids (SEQ ID NO:2). The open reading frame encoding this polypeptide is located from nucleotides 163 to 1137 of SEQ ID NO:1. Amino acids 1 to 19 of SEQ ID NO:2 form a cleavable signal peptide.

[0018] Another cDNA clone (ch1256) contains a 1941 basepair insert (SEQ ID NO:3) that encodes a polypeptide of 435 amino acids (SEQ ID NO:4). The open reading frame encoding this polypeptide is located from nucleotides 262 to nucleotide 1566 of SEQ ID NO:3. Amino acids 1 to 24 of SEQ ID NO:4 form a cleavable signal peptide.

[0019] Yet another cDNA clone (ch1284) contains a 1839 basepair insert (SEQ ID NO:5) that encodes a polypeptide of 339 amino acids (SEQ ID NO:6). The open reading frame encoding this polypeptide is located from nucleotides 40 to 1056 of SEQ ID NO:5. Amino acids 1 to 25 of SEQ ID NO:6 form a cleavable signal peptide.

[0020] Even another cDNA clone (ch1297) contains a 1831 basepair insert (SEQ ID NO:7) that encodes a polypeptide of 399 amino acids (SEQ ID NO:8). The open reading frame encoding this polypeptide is located from nucleotides 90 to 1286 of SEQ ID NO:7. Amino acids 1-19 of SEQ ID NO:8 form a cleavable signal peptide.

[0021] Still another cDNA clone (ch1233) contains a 4222 basepair insert (SEQ ID NO:9) that encodes a polypeptide of 709 amino acids (SEQ ID NO:10). The open reading frame encoding this polypeptide is located from nucleotides 238 to 2367 of SEQ ID NO:9. The open reading frame does not encode a cleavable signal peptide.

[0022] Another cDNA clone (ch 050) contains a 960 base pair inserts (SEQ ID NO:11) that encodes a polypeptide of 240 amino acids (SEQ ID NO:12). The open reading frame encoding this polypeptide is located from nucleotide 78 to 798. Amino acids 20 to 40 of the polypeptide contain a potential non-cleavable signal peptide and/or a transmembrane domain.

[0023] A further cDNA clone (ch1001) contains a 2832 bp insert (SEQ ID NO:13) that encodes a polypeptide of 613 amino acids (SEQ ID NO:14). The open reading frame encoding this polypeptide is located from nucleotide 317 to 2155. Amino acids 1 to 23 of the polypeptide contain a cleavable signal peptide.

[0024] Yet another cDNA clone (ch1007) contains a 3030 bp insert (SEQ ID NO:15) that encodes a polypeptide of 285 amino acids (SEQ ID NO:16). The open reading frame encoding this polypeptide is located from nucleotide 31 to 885. Amino acids 1 to 24 of the polypeptide contain a cleavable signal peptide.

[0025] Another cDNA clone (ch1035) contains a 2133 bp insert (SEQ ID NO:17) that encodes a polypeptide of 483 amino acids (SEQ ID NO:18). The open reading frame encoding this polypeptide is located from nucleotide 185 to 1633. Amino acids 1 to 20 of the polypeptide contain a cleavable signal peptide.

[0026] Still another cDNA clone (ch1063) contains a 1590 bp insert (SEQ ID NO:19) that encodes a polypeptide of 289 amino acids (SEQ ID NO:20). The open reading frame encoding this polypeptide is located from nucleotide 100 to 966. Amino acids 1 to 22 of the polypeptide contain a cleavable signal peptide.

[0027] Another cDNA clone (ch1572) contains a 1994 bp insert (SEQ ID NO:21) that encodes a polypeptide of 585 amino acids (SEQ ID NO:22). The open reading frame is located from nucleotides 132 to 1886. A hydrophobic stretch is found at positions 14 to 33, which can act as a signal sequence, and is followed by a potential signal peptidase cleavage site between amino acids 33 and 34.

[0028] Yet another cDNA clone (ch1569) contains a 1340 bp insert (SEQ ID NO:23) that encodes a polypeptide of 280 amino acids (SEQ ID NO:24). The open reading frame is located from nucleotide 79 to 919. Hydrophobic stretches are located at positions 1 to 20 and 180 to 206.

[0029] A further cDNA clone (ch1570) contains a 1011 bp insert (SEQ ID NO:25) that encodes a polypeptide of 286 amino acids (SEQ ID NO:26). The open reading frame is located from nucleotide 128 to 986. Hydrophobic stretches are found at amino acids 27 to 53, 61 to 86, 96 to 118, 206 to 246, and 257 to 279.

[0030] A still further cDNA clone (ch1529) contains a 2027 bp insert (SEQ ID NO:27) that encodes a polypeptide of 340 amino acids (SEQ ID NO:28). The open reading frame is located from nucleotide 270 to 1284. Hydrophobic stretches are found at amino acids 19 to 44, 144 to 164, 180 to 223, 231 to 255, and 260 to 280.

[0031] A further cDNA clone (ch1515) contains a 2390 bp insert (SEQ ID NO:29) that encodes a polypeptide of 347 amino acids (SEQ ID NO:30). A hydrophobic stretch of 30 amino acids is found at amino acid positions 55 to 85

[0032] The present invention provides both full-length and mature forms of the disclosed proteins. Full-length forms of the proteins have the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30. In the case of proteins which are membrane-bound, such as cell surface receptor proteins, soluble forms of the proteins can be obtained by deleting the nucleotide sequences which encode part or all of the intracellular and transmembrane domains of the protein and expressing a fully secreted form of the protein in a host cell. For example, the full-length forms of the proteins can be processed enzymatically to remove the signal sequence, resulting in mature forms of the proteins.

[0033] Other domains with predicted functions can also be identified. For example, transmembrane domains can be identified by examination of the amino acid sequences disclosed herein. A transmembrane domain typically contains a long stretch of 15-30 hydrophobic amino acids. Techniques for identifying intracellular and transmembrane domains, such as homology searches, can be used to identify such domains in proteins of the invention using amino acid and polynucleotide sequences disclosed herein.

[0034] Secreted proteins of the invention have a variety of uses. For example, the proteins can be used in assays to determine biological activities, such as cytokine, cell proliferation, or cellular differentiation activities, tissue growth or regeneration, activin or inhibin activity, chemotactic or chemokinetic activity, hemostatic or thrombolytic activity, receptor/ligand activity, tumor inhibition, or anti-inflammatory activity. Assays for these activities are known in the art, as disclosed below.

[0035] Proteins of the invention can also be used as biomarkers, to identify tissues or cell types which express the proteins, or to identify a stage- or disease-specific alteration in protein expression. Proteins of the invention can be used in protein interaction assays, to identify ligands or binding proteins. Compounds which affect the biological activities of the secreted proteins or their ability to interact with specific ligands can be identified using proteins of the invention in screening assays, such as the yeast two-hybrid assay. Proteins and antibodies of the invention can also be used to design diagnostic tests and therapeutic compositions for diseases which may be associated with altered expression of these proteins.

[0036] Polynucleotide molecules which encode the proteins disclosed herein can be used to propagate additional copies of the polynucleotides or to express proteins, polypeptides, or fusion proteins of the invention. The polynucleotide molecules disclosed herein can also be used, for example, as biomarkers for tissues or chromosomes, as molecular weight markers for DNA gels, to elicit immune responses, such as the formation of antibodies against single- or double-stranded DNA, and in DNA-ligand interaction assays, to detect proteins or other molecules which interact with the polynucleotide sequences.

[0037] Disease states may be associated with alterations in the expression of genes which encode proteins of the invention. Polynucleotide sequences disclosed herein can thus be used to determine the involvement of any of these sequences in disease states. For example, a gene in a diseased cell can be sequenced and compared with a wild-type coding sequence of the invention. Alternatively, nucleotide probes can be constructed and used to detect normal or mutant forms of mRNA in a diseased cell. Polynucleotide molecules of the invention can also be used to design diagnostic tests and therapeutic compositions for diseases which may be associated with altered expression of these genes.

Polypeptide Fragments

[0038] The invention provides polypeptide fragments of each of the disclosed proteins. Polypeptide fragments of the invention can comprise at least 8, 10, 12, 15, 18, 19, 20, 25, 50, 75, 100, 125, 130, 135, 140, 145, 150, 200, 250, 300, or 320 contiguous amino acids selected from SEQ ID NO:2. One preferred polypeptide fragment comprises amino acids 1-19 of SEQ ID NO:2.

[0039] Other polypeptide fragments can comprise at least 8, 10, 12, 15, 20, 24, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, or 430 contiguous amino acids of SEQ ID NO:4. A preferred polypeptide fragment comprises amino acids 1-24 of SEQ ID NO:4.

[0040] Still other polypeptide fragments can comprise at least 8, 10, 12, 15, 20, 25, 30, 50, 75, 100, 150, 200, 250, 300, or 330 contiguous amino acids of SEQ ID NO:6. A preferred polypeptide fragment comprises amino acids 1-25 of SEQ ID NO:6.

[0041] Even other polypeptide fragments can comprise at least 8, 10, 12, 15, 19, 20, 25, 30, 50, 75, 100, 150, 200, 250, 300, 350, or 375 contiguous amino acids of SEQ ID NO:8. A preferred polypeptide fragment comprises amino acids 1-19 of SEQ ID NO:8.

[0042] Yet other polypeptide fragments can comprise at least 8, 10, 12, 15, 20, 25, 30, 50, 52, 73, 75, 100, 150, 175, 180, 190, 200, 230, or 231 contiguous amino acids selected from amino acids 1-53, 137-210, 291-521, or 516-709 of SEQ ID NO:10, or at least 15, 16, 17, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 contiguous amino acids selected from amino acids 45-145 of SEQ ID NO:10, or at least 8, 10, 12, 15, 20, 25, 30, 50, 75, 100, 150, 250, 300, 350, 400, 450, 500, 550, 600, 650, or 700 contiguous amino acids of SEQ ID NO:10.

[0043] Other polypeptide fragments can comprise at least 8, 10, 12, 15, 18, 19, 20, 25, 50, 75, 100, 125, 130, 140, 145, 150, 200, 250, 300, 350, 400, 450, 500, 550, or 580 contiguous amino acids of SEQ ID NO:22. Preferred fragments comprise amino acids 14-33 and amino acids 34-585.

[0044] Yet other polypeptide fragments can comprise at least 8, 10, 12, 15, 18, 19, 20, 25, 50, 75, 100, 125, 130, 140, 145, 150, 200, 250, and 275 contiguous amino acids of SEQ ID NO:24. Preferred fragments comprise amino acids 1-20; amino acids 21-280; and amino acids 180-206.

[0045] Other polypeptide fragments can comprise at least 8, 10, 12, 15, 18, 19, 20, 25, 50, 75, 100, 125, 130, 140, 145, 150, 200, 250, 275, and 280 contiguous amino acids of SEQ ID NO:26. Preferred fragments comprise amino acids 27-53; 62-86; 96-118; 206-246; and 257-279.

[0046] Further polypeptide fragments can comprise at least 8, 10, 12, 15, 18, 19, 20, 25, 50, 75, 100, 125, 130, 140, 145, 150, 200, 250, 300, 325, or 330 contiguous amino acids of SEQ ID NO:28. Preferred fragments comprise amino acids 19-44; 144-164; 180-223; 231-255; and 260-280.

[0047] Other preferred fragments can comprise at least 8, 10, 12, 15, 18, 19, 20, 25, 50, 75, 100, 125, 130, 140, 145, 150, 200, 250, 300, 325, 340 or 345 contiguous amino acids of SEQ ID NO:30. A preferred fragment comprises amino acids 55-85.

Biologically Active Variants

[0048] Variants of the secreted proteins and polypeptides disclosed herein can also occur. Variants can be naturally or non-naturally occurring. Naturally occurring variants are found in humans or other species and comprise amino acid sequences which are substantially identical to the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30. Species homologs of the secreted proteins can be obtained using subgenomic polynucleotides of the invention, as described below, to make suitable probes or primers to screening cDNA expression libraries from other species, such as mice, monkeys, yeast, or bacteria, identifying cDNAs which encode homologs of the secreted proteins, and expressing the cDNAs as is known in the art.

[0049] Non-naturally occurring variants which retain substantially the same biological activities as naturally occurring protein variants, such as cytokine, cell proliferation, or cellular differentiation activities, tissue growth or regeneration, activin or inhibin activity, chemotactic or chemokinetic activity, hemostatic or thrombolytic activity, receptor/ligand activity, tumor inhibition, or anti-inflammatory activity, are also included here. Preferably, naturally or non-naturally occurring variants have amino acid sequences which are at least 85%, 90%, or 95% identical to the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30. More preferably, the molecules are at least 98% or 99% identical. Percent identity is determined using the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1. The Smith-Waterman homology search algorithm is taught in Smith and Waterman, Adv. Appl. Math. (1981) 2:482-489.

[0050] Guidance in determining which amino acid residues can be substituted, inserted, or deleted without abolishing biological or immunological activity can be found using computer programs well known in the art, such as DNASTAR software. Preferably, amino acid changes in secreted-protein variants are conservative amino acid changes, i.e., substitutions of similarly charged or uncharged amino acids. A conservative amino acid change involves substitution of one of a family of amino acids which are related in their side chains. Naturally occurring amino acids are generally divided into four families: acidic (aspartate, glutamate), basic (lysine, arginine, histidine), non-polar (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and uncharged polar (glycine, asparagine, glutamine, cystine, serine, threonine, tyrosine) amino acids. Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids.

[0051] It is reasonable to expect that an isolated replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, a threonine with a serine, or a similar replacement of an amino acid with a structurally related amino acid will not have a major effect on the biological properties of the resulting variant. Whether an amino acid change results in a functional secreted protein or polypeptide can readily be determined by testing the altered protein or polypeptide in a functional assay, for example, as disclosed in U.S. Pat. No. 5,654,173 and described in detail below.

[0052] Variants of the secreted proteins disclosed herein include glycosylated forms, aggregative conjugates with other molecules, and covalent conjugates with unrelated chemical moieties. Covalent variants can be prepared by linking functionalities to groups which are found in the amino acid chain or at the N- or C-terminal residue, as is known in the art. Variants also include allelic variants, species variants, and muteins. Truncations or deletions of regions which do not affect functional activity of the proteins are also variants.

[0053] A subset of mutants, called muteins, is a group of polypeptides in which neutral amino acids, such as serines, are substituted for cysteine residues which do not participate in disulfide bonds. These mutants may be stable over a broader temperature range than native secreted proteins. See Mark et al., U.S. Pat. No. 4,959,314.

[0054] Preferably, amino acid changes in the secreted protein or polypeptide variants are conservative amino acid changes, i.e., substitutions of similarly charged or uncharged amino acids. A conservative amino acid change involves substitution of one of a family of amino acids which are related in their side chains. Naturally occurring amino acids are generally divided into four families: acidic (aspartate, glutamate), basic (lysine, arginine, histidine), non-polar (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and uncharged polar (glycine, asparagine, glutamine, cystine, serine, threonine, tyrosine) amino acids. Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids.

[0055] It is reasonable to expect that an isolated replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, a threonine with a serine, or a similar replacement of an amino acid with a structurally related amino acid will not have a major effect on the biological properties of the resulting secreted protein or polypeptide variant. Properties and functions of secreted protein or polypeptide variants are of the same type as a secreted protein or polypeptide comprising amino acid sequences encoded by the nucleotide sequence shown in SEQ ID NO:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, and 29, although the properties and functions of variants can differ in degree. Whether an amino acid change results in a secreted protein or polypeptide variant with the appropriate differential expression pattern can readily be determined. For example, nucleotide probes can be selected from the marker gene sequences disclosed herein and used to detect corresponding mRNA in Northern blots or in tissue sections, as is known in the art. Alternatively, antibodies which specifically bind to protein products of genes can be used to detect expression of secreted proteins or variants thereof.

[0056] Secreted protein variants include glycosylated forms, aggregative conjugates with other molecules, and covalent conjugates with unrelated chemical moieties. Secreted protein variants also include allelic variants, species variants, and muteins. Truncations or deletions of regions which do not affect the differential expression of the secreted protein genes are also variants. Covalent variants can be prepared by linking functionalities to groups which are found in the amino acid chain or at the N- or C-terminal residue, as is known in the art.

[0057] It will be recognized in the art that some amino acid sequence of the polypeptide of the invention can be varied without significant effect on the structure or function of the protein. If such differences in sequence are contemplated, it should be remembered that there are critical areas on the protein which determine activity. In general, it is possible to replace residues that form the tertiary structure, provided that residues performing a similar function are used. In other instances, the type of residue may be completely unimportant if the alteration occurs at a non-critical region of the protein. The replacement of amino acids can also change the selectivity of binding to cell surface receptors. Ostade et al., Nature 361:266-268 (1993) describes certain mutations resulting in selective binding of TNF-alpha to only one of the two known types of TNF receptors. Thus, the polypeptides of the present invention may include one or more amino acid substitutions, deletions or additions, either from natural mutations or human manipulation.

[0058] The invention further includes variations of the disclosed polypeptide which show comparable expression patterns or which include antigenic regions. Such mutants include deletions, insertions, inversions, repeats, and type substitutions. Guidance concerning which amino acid changes are likely to be phenotypically silent can be found in Bowie, J. U., et al., “Deciphering the Message in Protein Sequences: Tolerance to Amino Acid Substitutions,” Science 247:1306-1310 (1990).

[0059] Of particular interest are substitutions of charged amino acids with another charged amino acid and with neutral or negatively charged amino acids. The latter results in proteins with reduced positive charge to improve the characteristics of the disclosed protein. The prevention of aggregation is highly desirable. Aggregation of proteins not only results in a loss of activity but can also be problematic when preparing pharmaceutical formulations, because they can be immunogenic. (Pinckard et al., Clin. Exp. Immunol. 2:331-340 (1967); Robbins et al., Diabetes 36:838-845 (1987); Cleland et al., Crit. Rev. Therapeutic Drug Carrier Systems 10:307-377 (1993)).

[0060] Amino acids in the polypeptides of the present invention that are essential for function can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham and Wells, Science 244:1081-1085 (1989)). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity such as receptor binding, or in vitro proliferative activity. Sites that are critical for ligand-receptor binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith et al., J. Mol. Biol. 224:899-904 (1992) and de Vos et al. Science 255:306-312 (1992)).

[0061] As indicated, changes are preferably of a minor nature, such as conservative amino acid substitutions that do not significantly affect the folding or activity of the protein. Of course, the number of amino acid substitutions a skilled artisan would make depends on many factors, including those described above. Generally speaking, the number of substitutions for any given polypeptide will not be more than 50, 40, 30, 25, 20, 15, 10, 5 or 3.

[0062] Non-limiting examples of amino acid substitutions include substituting the amino acids at one or both of positions 33 and 34 of SEQ ID NO:22, thereby eliminating the potential signal peptidase cleavage site; and substituting one or more of the amino acids at positions 8, 130, 134, 145 and 151 of SEQ ID NO:26; positions 39, 56, 62, 102 and 107 of SEQ ID NO;28; and positions 147, 155 and 237 of SEQ ID NO:30, thereby preventing N-glycosylation at the substituted site(s).

Fusion Proteins

[0063] Fusion proteins comprising proteins or polypeptide fragments of the invention also be constructed. Fusion proteins are useful for generating antibodies against amino acid sequences and for use in various assay systems. For example, fusion proteins can be used to identify proteins which interact with a protein of the invention or which interfere with its biological function. Physical methods, such as protein affinity chromatography, or library-based assays for protein-protein interactions, such as the yeast two-hybrid or phage display systems, can also be used for this purpose. Such methods are well known in the art and can also be used as drug screens. Fusion proteins comprising a signal sequence and/or a transmembrane domain of one or more of the disclosed proteins can be used to target other protein domains to cellular locations in which the domains are not normally found, such as bound to a cellular membrane or secreted extracellularly.

[0064] A fusion protein comprises two protein segments fused together by means of a peptide bond. Amino acid sequences for use in fusion proteins of the invention can be selected from the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30 or from biologically active variants of those sequences, such as those described above. The first protein segment can consist of a full-length secreted protein.

[0065] Other first protein segments can consist of at least 8, 10, 12, 15, 18, 19, 20, 25, 50, 75, 100, 125, 130, 135, 140, 145, 150, 200, 250, 300, or 320 contiguous amino acids selected from SEQ ID NO:2 or at least amino acids 1-19 of SEQ ID NO:2.

[0066] Still other first protein segments can consist of at least 8, 10, 12, 15, 20, 24, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, or 430 contiguous amino acids of SEQ ID NO:4 or at least amino acids 1-24 of SEQ ID NO:4.

[0067] Yet other first protein segments can consist of at least 8, 10, 12, 15, 20, 25, 30, 50, 75, 100, 150, 200, 250, 300, or 330 contiguous amino acids of SEQ ID NO:6 or at least amino acids 1-25 of SEQ ID NO:6.

[0068] Even other first protein segments can consist of at least 8, 10, 12, 15, 19, 20, 25, 30, 50, 75, 100, 150, 200, 250, 300, 350, or 375 contiguous amino acids of SEQ ID NO:8 or at least amino acids 1-19 of SEQ ID NO:8.

[0069] Other first protein segments can consist of at least 8, 10, 12, 15, 20, 25, 30, 50, 52, 73, 75, 100, 150, 175, 180, 190, 200, 230, or 231 contiguous amino acids selected from amino acids 1-53, 137-210, 291-521, or 516-709 of SEQ ID NO:10, at least 15, 16, 17, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 contiguous amino acids selected from amino acids 45-145 of SEQ ID NO 10, or at least 8, 10, 12, 15, 20, 25, 30, 50, 75, 100, 150, 250, 300, 350, 400, 450, 500, 550, 600, 650, or 700 contiguous amino acids of SEQ ID NO:10.

[0070] Other first protein segments can consist of at least 8, 10, 12, 15, 20, 24, 25, 50, 75, 100, 125, 130, 150, 175, 200, 225, 230, 235 or 239 contiguous amino acids of SEQ ID NO:12, at least 8, 10, 12, 15, 20, 24, 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 550, 600, 605 or 610 contiguous amino acids of SEQ ID NO:14, or at least 8, 10, 12, 15, 20, 24, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275 or 280 contiguous amino acids of SEQ ID NO:16.

[0071] Other first protein segments can consist of at least 8, 10, 12, 15, 20, 24, 25, 50, 75, 100, 125, 130, 150, 175, 200, 250, 275, 300, 350, 400, 425, 450, 475 or 480 contiguous amino acids of SEQ ID NO:18, or at least 8, 10, 12, 15, 20, 24, 25, 50, 75, 100, 125, 150, 200, 225, 250, 275, 280 or 285 contiguous amino acids of SEQ ID NO:20.

[0072] The second protein segment can be a full-length protein or a polypeptide fragment. Proteins commonly used in fusion protein construction include β-galactosidase, β-glucuronidase, green fluorescent protein (GFP), autofluorescent proteins, including blue fluorescent protein (BFP), glutathione-S-transferase (GST), luciferase, horseradish peroxidase (HRP), and chloramphenicol acetyltransferase (CAT). Additionally, epitope tags can be used in fusion protein constructions, including histidine (His) tags, FLAG tags, influenza hemagglutinin (HA) tags, Myc tags, VSV-G tags, and thioredoxin (Trx) tags. Other fusion constructions can include maltose binding protein (MBP), S-tag, Lex a DNA binding domain (DBD) fusions, GAL4 DNA binding domain fusions, and herpes simplex virus (HSV) BP16 protein fusions.

[0073] These fusions can be made, for example, by covalently linking two protein segments or by standard procedures in the art of molecular biology. Recombinant DNA methods can be used to prepare fusion proteins, for example, by making a DNA construct which comprises coding sequences selected from SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29 in proper reading frame with nucleotides encoding the second protein segment and expressing the DNA construct in a host cell, as is known in the art. Many kits for constructing fusion proteins are available from companies that supply research labs with tools for experiments, including, for example, Promega Corporation (Madison, Wis.), Stratagene (La Jolla, Calif.), Clontech (Mountain View, Calif.), Santa Cruz Biotechnology (Santa Cruz, Calif.), MBL International Corporation (MIC; Watertown, Mass.), and Quantum Biotechnologies (Montreal, Canada; 1-888-DNA-KITS).

Isolation and Production of Secreted Proteins

[0074] Secreted proteins can be extracted from human cells, such as bone marrow, spleen, thymus, or peripheral blood lymphocytes, using standard biochemical methods. These methods include, but are not limited to, size exclusion chromatography, ammonium sulfate fractionation, ion exchange chromatography, affinity chromatography, crystallization, electrofocusing, and preparative gel electrophoresis. An isolated and purified secreted protein or polypeptide is separated from other compounds which normally associate with the protein or polypeptide in a cell, such as other proteins, carbohydrates, lipids, or subcellular organelles. A preparation of isolated and purified secreted proteins or polypeptides is at least 80% pure; preferably, the preparations are 90%, 95%, or 99% pure. Purity of the preparations can be assessed by any means known in the art. For example, the purity of a preparation can be assessed by examining electrophoretograms of protein or polypeptide preparations at several pH values and at several polyacrylamide concentrations, as is known in the art.

[0075] Proteins, fusion proteins, or polypeptides of the invention can be produced by recombinant DNA methods. For production of recombinant proteins, fusion proteins, or polypeptides, coding sequences selected from the nucleotide sequences shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29 can be expressed in prokaryotic or eukaryotic host cells using expression systems known in the art. These expression systems include bacterial, yeast, insect, and mammalian cells (see below).

[0076] The resulting expressed protein can then be purified from the culture medium or from extracts of the cultured cells using purification procedures known in the art. For example, for proteins fully secreted into the culture medium, cell-free medium can be diluted with sodium acetate and contacted with a cation exchange resin, followed by hydrophobic interaction chromatography. Using this method, the desired protein or polypeptide is typically greater than 95% pure. Further purification can be undertaken, using, for example, any of the techniques listed above.

[0077] It may be necessary to modify a protein produced in yeast or bacteria, for example by phosphorylation or glycosylation of the appropriate sites, in order to obtain a functional protein. Such covalent attachments can be made using known chemical or enzymatic methods.

[0078] Proteins or polypeptides of the invention can also be expressed in cultured host cells in a form which will facilitate purification. For example, a secreted protein or polypeptide can be expressed as a fusion protein comprising, for example, maltose binding protein, glutathione-S-transferase, or thioredoxin, and purified using a commercially available kit. Kits for expression and purification of such fusion proteins are available from companies such as New England BioLabs, Pharmacia, and Invitrogen. Proteins, fusion proteins, or polypeptides can also be tagged with an epitope, such as a “Flag” epitope (Kodak), and purified using an antibody which specifically binds to that epitope.

[0079] The coding sequences disclosed herein can also be used to construct transgenic animals, such as cows, goats, pigs, or sheep. Female transgenic animals can then produce proteins, polypeptides, or fusion proteins of the invention in their milk. Methods for constructing such animals are known and widely used in the art.

[0080] Alternatively, synthetic chemical methods, such as solid phase peptide synthesis, can be used to synthesize a secreted protein or polypeptide. General means for the production of peptides, analogs or derivatives are outlined in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins—A Survey of Recent Developments, B. Weinstein, ed. (1983). Substitution of D-amino acids for the normal L-stereoisomer can be carried out to increase the half-life of the molecule. Variants can be similarly produced.

Antibodies

[0081] Isolated and purified proteins, polypeptides, variants, or fusion proteins can be used as immunogens, to obtain preparations of antibodies which specifically bind to epitopes of the disclosed proteins. The antibodies can be used, inter alia, to detect wild-type secreted protein or secreted protein complexes in human tissue and fractions thereof. The antibodies can also be used to detect the presence of mutations in a gene which result in under- or over-expression of a secreted protein of the invention or in expression of a secreted protein with altered size or electrophoretic mobility.

[0082] Any type of antibody known in the art can be generated to bind specifically to epitopes of secreted proteins of the invention. For example, preparations of polyclonal and monoclonal antibodies can be made using standard methods which are well known in the art. Single-chain antibodies can also be prepared. Single-chain antibodies which specifically bind to epitopes of the disclosed proteins can be isolated, for example, from single-chain immunoglobulin display libraries, as is known in the art. The library is “panned” against a disclosed amino acid sequence, and a number of single chain antibodies which bind with high-affinity to different epitopes of a protein of the invention can be isolated. Hayashi et al., 1995, Gene 160:129-30. Single-chain antibodies can also be constructed using a DNA amplification method, such as the polymerase chain reaction (PCR), using hybridoma cDNA as a template. Thirion et al., 1996, Eur. J. Cancer Prev. 5:507-11.

[0083] Single-chain antibodies can be mono- or bispecific, and can be bivalent or tetravalent. Construction of tetravalent, bispecific single-chain antibodies is taught, for example, in Coloma and Morrison, 1997, Nat. Biotechnol. 15:159-63. Construction of bivalent, bispecific; single-chain antibodies is taught inter alia in Mallender and Voss. 1994, J. Biol. Chem. 269:199-206.

[0084] A nucleotide sequence encoding a single-chain antibody can be constructed using manual or automated nucleotide synthesis, cloned into an expression construct using standard recombinant DNA methods, and introduced into a cell to express the coding sequence, as described below. Alternatively, single-chain antibodies can be produced directly using, for example, filamentous phage technology. Verhaar et al., 1995, Int. J. Cancer 61:497-501; Nicholls et al., 1993, J. Immunol. Meth. 165:81-91.

[0085] Monoclonal and other antibodies can also be “humanized” in order to prevent a patient from mounting an immune response against the antibody when it is used therapeutically. Such antibodies may be sufficiently similar in sequence to human antibodies to be used directly in therapy or may require alteration of a few key residues. Sequence differences between, for example, rodent antibodies and human sequences can be minimized by replacing residues which differ from those in the human sequences, for example, by site directed mutagenesis of individual residues, or by grafting of entire complementarily determining regions. Alternatively, one can produce humanized antibodies using recombinant methods, as described in GB2188638B. Antibodies which specifically bind to secreted protein epitopes can contain antigen binding sites which are either partially or fully humanized, as disclosed in U.S. Pat. No. 5,565,332.

[0086] Rodents, such as mice and rats, can be genetically engineered to produce a large repertoire of human antibodies. Segments of human immunoglobulin loci can be introduced into the germlines of these rodents. Either miniloci, containing 1-2 VH segments, or large continuous fragments of human heavy and light immunoglobulin loci can be used. If desired, gene targeting can be used to create rodents which do not make rodent antibodies. The engineered rodents produce fully human antibodies. In particular, human monoclonal antibodies with high affinity and specificity against a wide variety of antigens, including human antigens, can be produced. Methods of producing fully human antibodies from transgenic rodents are taught, for example, in Wagner et al. Eur. J. Immunol. 24: 2672-81 (1994); Lonberg et al., Nature 368: 856 59 (1994); Green et al., Nature Genet. 7: 13-21 (1994); Jakobovits, Curr. Opin. Biotechnol. 6: 561-66 (1995); Jakobovits et al, Ann. N.Y Acad. Sci. 764: 525-35 (1995); Bruggemann & Neuberger, Immunol. Today 17: 391-97 (1996); and Mendez et al., Nature Genet. 15: 146-56(1997).

[0087] Other types of antibodies can be constructed and used therapeutically. For example, chimeric antibodies can be constructed as disclosed in WO 93/03151. Binding proteins which are derived from immunoglobulins and which are multivalent and multispecific, such as the “diabodies” described in WO 94/13804, can also be prepared.

[0088] Secreted protein-specific antibodies specifically bind to epitopes present in a full-length secreted protein having an amino acid sequence as shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18 or 20, to polypeptide fragments, or to variants, either alone or as part of a fusion protein. Preferably, the epitopes are not present in other human proteins. Typically, at least 6, 8, 10, or 12 contiguous amino acids are required to form an epitope. However, epitopes which involve non-contiguous amino acids may require more, e.g., at least 15, 25, or 50 amino acids.

[0089] Antibodies which specifically bind to epitopes of the disclosed proteins, polypeptides, fusion proteins, or biologically active variants can be used in immunochemical assays, including but not limited to Western blots, ELISAs, radioimmunoassays, immunohistochemical assays, immunoprecipitations, or other immunochemical assays known in the art. Typically, antibodies of the invention provide a detection signal at least 5-, 10-, or 20-fold higher than a detection signal provided with other proteins when used in such immunochemical assays. Preferably, antibodies which specifically bind to epitopes of the disclosed proteins do not detect other proteins in immunochemical assays and can immunoprecipitate a secreted protein or polypeptide of the invention from solution.

[0090] Antibodies can be purified by methods well known in the art. Preferably, the antibodies are affinity purified, by passing the antibodies over a column to which a protein, polypeptide, variant, or fusion protein of the invention is bound. The bound antibodies can then be eluted from the column, for example, using a buffer with a high salt concentration.

Polynucleotide Sequences

[0091] Genes which encode the secreted proteins of the invention have the coding sequences shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29. Polynucleotide molecules of the invention contain less than a whole chromosome and can be single- or double-stranded. Preferably, the polynucleotide molecules are intron-free. Polynucleotide molecules of the invention can comprise at least 11, 15, 18, 21, 30, 33, 42, 54, 60, 66, 72, 84, 90, 10, 120, 140, 160, 180, 200, 240, 300, 330, 400, 420, 500, 540, 600, 660, 700, 720, 800, 840, 900, 960, 1000, 1100, or 1200 or more contiguous nucleotides selected from nucleotides 109-1313 of SEQ ID NO:1, at least 37, 42, 54, 60, 66, 72, 84, 90, 10, 120, 140; 160, 180, 200, 240, 300, 330, 400, 420, 500, 540, 600, 660, 700, 720, 800, 840, 900, 960, 1000, 1100, 1200, or 1230 contiguous nucleotides selected from nucleotides 84 to 1313 of SEQ ID NO:1, at least 69, 72, 84, 90, 10, 120, 140, 160, 180, 200, 240, 300, 330, 400, 420, 500, 540, 600, 660, 700, 720, 800, 840, 900, 960, 1000, 1100, 1200, 1250, or 1300 contiguous nucleotides selected from SEQ ID NO:1, the 1313 contiguous nucleotides of SEQ ID NO:1, or the complements thereof.

[0092] Other polynucleotide molecules of the invention can comprise at least 11, 15, 18, 21, 30, 33, 42, 54, 60, 66, 72, 84, 90, 10, 120, 140, 160, 180, 200, 240, 300, 330, 400, 420, 500, 540, 600, 660, 700, 720, or 800 contiguous nucleotides selected from nucleotides 1-818 of SEQ ID NO:3, at least 11, 15, 18, 21, 30, 33, 42, 54, 60, 66, 72, 84, 90, 100, 120, 140, 160, or 180 contiguous nucleotides selected from nucleotides 1762-1941 of SEQ ID NO:3 at least 550, 600, 660, 700, 720, 800, 840, 900, 960, 1000, 1100, 1200, 1250, 1295, 1300, 1350, 1400, or 1411 contiguous nucleotides selected from SEQ ID NO:3, at least 30, 33, 42, 54, 60, 66, 72, 84, 90, 10, 120, 140, 160, 180, 200, 240, 300, 330, 400, 420, 500, 550, 600, 660, 700, 720, 800, 840, 900, 960, 1000, 1100, 1200, 1250, 1295, 1300, 1350 , 1400, or 1420 contiguous nucleotides selected from nucleotides 1-1425 of SEQ ID NO:3, at least 68, 72, 84, 90, 10, 120, 140, 160, 180, 200, 240, or 300 contiguous nucleotides selected from nucleotides 1637-1941 of SEQ ID NO:3, at least 97, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 550, 600, 660, 700, 720, 800, 840, 900, 960, 1000, 1100, 1200, 1250, 1295, 1300, 1350, 1400, 1450, 1500, 1550, 1600, or 1650 contiguous nucleotides selected from nucleotides 1-1652 of SEQ ID NO:3, at least 97, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 550, 600, 660, 700, 720, 800, 840, 900, 960, 1000, 1100, or 1200 contiguous nucleotides selected from nucleotides 262-1556 of SEQ ID NO:3, the 1941 contiguous nucleotides of SEQ ID NO:3, or the complements thereof.

[0093] Still other polynucleotide molecules of the invention can comprise at least 11 contiguous nucleotides selected from nucleotides molecules 1-32 of SEQ ID NO:5, at least 11, 15, 18, 21, 30, 33, 42, 54, 60, 66; 72, 84, 90, 10, 120, 140, 160, 180, 200, 240, 300, 330, 400, 420, 500, 540, 600, or 640 contiguous nucleotides selected from nucleotides 191-1839 of SEQ ID NO:5, at least 180, 200, 250, 300, 350, 400, 450, 500, 550, 600, 660, 700, 720, 800, 840, 900, 960, 1000, 1017, 1100, 1200, 1250, 1295, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, or 1800 contiguous nucleotides selected from SEQ ID NO:5, the 1839 contiguous nucleotides of SEQ ID NO:5, or the complements thereof.

[0094] Even other polynucleotide molecules of the invention can comprise at least 27, 30, 33, 42, 54, 57, 60, 66, 72, 84, 90, 10, 120, 140, 160, 180, 200, 240, 300, 330, 400, 420, 500, 540, 600, 700, 720, 800, 840, 900, 960, 1000, 1017, 1100, 1200, 1250, 1295, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, or 1800 contiguous nucleotides selected from SEQ ID NO:7, at least 11, 15, 18, 21, 30, 33, 42, 54, 57, 60, 66, 72, 84, 90, 10, 120, 140, 160, 180, 200, 240, 300, 330, 400, 420, 500, 540, 600, 700, 720, 800, 840, 900, 960, 1000, 1017, 1100, 1197, 1200, 1250, 1295, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, or 1800 contiguous nucleotides selected from nucleotides 16-1831 of SEQ ID NO:7, the 1831 contiguous nucleotides of SEQ ID NO:7, or the complements thereof.

[0095] Other polynucleotide molecules of the invention can comprise at least 11, 15, 18, 21, 30, 33, 42, 54, 57, 60, 66, 72, 84, 90, 10, 120, 140, 160, 180, 200, 240, 300, 330, 400, 420, 500, 540, 600, 700, 720, 800, 840, 900, 960, 1000, 1017, 1100, 1197, 1200, 1250, 1295, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, or 4220 contiguous nucleotides selected from SEQ ID NO:9, the 4222 contiguous nucleotides of SEQ ID NO:9, or the complements thereof.

[0096] The complements of the nucleotide sequences shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29 are contiguous nucleotide sequences which form Watson-Crick base pairs with a contiguous nucleotide sequence as shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29. The complements of the nucleotide sequences shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29 (the antisense strand) can be used provide antisense oligonucleotides. Polynucleotide molecules of the invention also include molecules which encode single-chain antibodies which specifically bind to the disclosed proteins, ribozymes which specifically bind to mRNA encoding the disclosed proteins, and fusion proteins comprising amino acid sequences of the disclosed proteins.

[0097] Degenerate polynucleotide sequences which encode amino acid sequences of the secreted proteins and variants, as well as homologous nucleotide sequences which are at least 65%, 75%, 85%, 90%, 95%, 98%, or 99% identical to the nucleotide sequences shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29 are also polynucleotide molecules of the invention. Percent sequence identity is determined by any method known in the art, for example, using computer programs which employ the Smith-Waterman algorithm, such as the MPSRCH program (Oxford Molecular), using an affine gap search with the following parameters: a gap open penalty of 12 and a gap extension penalty of 1.

[0098] Typically, homologous polynucleotide sequences can be confirmed by hybridization under stringent conditions, as is known in the art. For example, using the following wash conditions: 2× SSC (0.3 M NaCl, 0.03 M sodium citrate, pH 7.0), 0.1% SDS, room temperature twice, 30 minutes each; then 2× SSC, 0.1% SDS, 50° C. once, 30 minutes; then 2× SSC, room temperature twice, 10 minutes each, homologous sequences can be identified which contain at most about 25-30% basepair mismatches. More preferably, homologous nucleic acid strands contain 15-25% basepair mismatches, even more preferably 5-15% basepair mismatches.

[0099] Species homologs of polynucleotide molecules which encode proteins of the invention can be identified by making suitable probes or primers and screening cDNA expression libraries from other species, such as mice, monkeys, yeast, or bacteria, as well as human cDNA expression libraries. It is well known that the Tm of a double-stranded DNA decreases by 1-1.5° C. with every 1% decrease in homology (Bonner et al., J. Mol. Biol. 81, 123 (1973). Homologous human polynucleotides or polynucleotides of other species can therefore be identified, for example, by hybridizing a putative homologous polynucleotide with a polynucleotide having the nucleotide sequence of SEQ ID NO:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29 to form a test hybrid, comparing the melting temperature of the test hybrid with the melting temperature of a hybrid of a polynucleotide consisting of a nucleotide sequence of SEQ ID NO:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29 and a perfectly complementary polynucleotide, and calculating the number or percent of basepair mismatches within the test hybrid.

[0100] Nucleotide sequences which hybridize to the coding sequences shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29 or their complements following stringent hybridization and/or wash conditions are also polynucleotide molecules of the invention. Stringent wash conditions are well known and understood in the art and are disclosed, for example, in Sambrook et al., Molecular Cloning A Laboratory Manual, 2d ed., 1989, at pages 9.50-9.51.

[0101] Typically, for stringent hybridization conditions a combination of temperature and salt concentration should be chosen that is approximately 12-20° C. below the calculated Tm of the hybrid under study. The Tm of a hybrid between a nucleotide sequence as shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29 and a polynucleotide sequence which is 65%, 75%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical can be calculated, for example, using the equation of Bolton and McCarthy, Proc. Natl. Acad. Sci. U.S.A. 48, 1390 (1962):

T _(m)=81.5° C.−16.6(log₁₀ [Na ⁺])+0.41(%G+C)−0.63(%formamide)−600/l),

[0102] where l=the length of the hybrid in basepairs.

[0103] Stringent wash conditions include, for example, 4× SSC at 65° C., or 50% formamide, 4× SSC at 42° C., or 0.5× SSC, 0.1% SDS at 65° C. Highly stringent wash conditions include, for example, 0.2× SSC at 65° C.

[0104] Polynucleotide molecules of the invention can be isolated and purified free from other nucleotide sequences using standard nucleic acid purification techniques. For example, restriction enzymes and probes can be used to isolate polynucleotide fragments which comprise nucleotide sequences encoding one or more of the secreted proteins disclosed herein. Isolated and purified polynucleotide molecules are in preparations which are free or at least 90% free of other molecules.

[0105] Complementary DNA (cDNA) molecules which encode secreted proteins of the invention are also polynucleotide molecules of the invention. cDNA molecules can be made with standard molecular biology techniques, using mRNA as a template. cDNA molecules can thereafter be replicated using molecular biology techniques known in the art and disclosed in manuals such as Sambrook et al., 1989. An amplification technique, such as the polymerase chain reaction (PCR), can be used to obtain additional copies of polynucleotide molecules of the invention, using either human genomic DNA or cDNA as a template.

[0106] Alternatively, synthetic chemistry techniques can be used to synthesize polynucleotide molecules of the invention. The degeneracy of the genetic code allows polynucleotide molecules with alternate nucleotide sequences to be synthesized which will encode a protein having an amino acid sequence as shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 or 30 or a biologically active variant of one of those proteins. All such polynucleotide molecules are within the scope of the present invention.

[0107] The invention also provides polynucleotide probes which can be used to detect complementary nucleotide sequences, for example, in hybridization protocols such as Northern or Southern blotting or in situ hybridizations. Polynucleotide probes of the invention comprise at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, or 40 or more contiguous nucleotides selected from SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29. Polynucleotide probes of the invention can comprise a detectable label, such as a radioisotopic, fluorescent, enzymatic, or chemiluminescent label.

[0108] Isolated genes corresponding to the cDNA sequences disclosed herein are also provided. Standard molecular biology methods can be used to isolate the corresponding genes using the cDNA sequences provided herein. These methods include preparation of probes or primers from the nucleotide sequences shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29 for use in identifying or amplifying the genes from human genomic libraries or other sources of human genomic DNA.

[0109] Polynucleotide molecules of the invention can also be used as primers to obtain additional copies of the polynucleotides, using polynucleotide amplification methods. Polynucleotide molecules can be propagated in vectors and cell lines using techniques well known in the art. Polynucleotide molecules can be on linear or circular molecules. They can be on autonomously replicating molecules or on molecules without replication sequences. They can be regulated by their own or by other regulatory sequences, as is known in the art.

Polynucleotide Constructs

[0110] Polynucleotide molecules comprising the coding sequences disclosed herein can be used in a polynucleotide construct, such as a DNA or RNA construct. Polynucleotide molecules of the invention can be used, for example, in an expression construct to express all or a portion of a secreted protein, variant, fusion protein, or single-chain antibody in a host cell. An expression construct comprises a promoter which is functional in a chosen host cell. The skilled artisan can readily select an appropriate promoter from the large number of cell type-specific promoters known and used in the art. The expression construct can also contain a transcription terminator which is functional in the host cell. The expression construct comprises a polynucleotide segment which encodes all or a portion of the desired protein. The polynucleotide segment is located downstream from the promoter. Transcription of the polynucleotide segment initiates at the promoter. The expression construct can be linear or circular and can contain sequences, if desired, for autonomous replication.

Host Cells

[0111] An expression construct can be introduced into a host cell. The host cell comprising the expression construct can be any suitable prokaryotic or eukaryotic cell. Expression systems in bacteria include those described in Chang et al., Nature (1978) 275: 615; Goeddel et al., Nature (1979) 281: 544; Goeddel et al., Nucleic Acids Res. (1980) 8: 4057; EP 36,776; U.S. Pat. No. 4,551,433; deBoer et al., Proc. Natl. Acad. Sci. USA (1983) 80: 21-25; and Siebenlist et al., Cell (1980) 20: 269.

[0112] Expression systems in yeast include those described in Hinnen et al., Proc. Natl. Acad. Sci. USA (1978) 75: 1929; Ito et al., J. Bacteriol. (1983) 153: 163; Kurtz et al., Mol. Cell. Biol. (1986) 6: 142; Kunze et al., J. Basic Microbiol. (1985) 25: 141; Gleeson et al., J. Gen. Microbiol. (1986) 132: 3459, Roggenkamp et al., Mol. Gen. Genet. (1986) 202: 302); Das et al., J Bacteriol. (1984) 158: 1165; De Louvencourt et al., J. Bacteriol. (1983) 154: 737, Van den Berg et al., Bio/Technology (1990) 8: 135; Kunze et al., J. Basic Microbiol. (1985) 25: 141;Cregg et al., Mol. Cell. Biol. (1985) 5: 3376; U.S. Pat. No. 4,837,148; U.S. Pat. No. 4,929,555; Beach and Nurse, Nature (1981) 300: 706; Davidow et al., Curr. Genet. (1985) 1p: 380; Gaillardin et al., Curr. Genet. (1985) 10: 49; Ballance et al., Biochem. Biophys. Res. Commun. (1983) 112: 284-289; Tilburn et al., Gene (1983) 26: 205-22;, Yelton et al., Proc. Natl. Acad. Sci. USA (1984) 81: 1470-1474; Kelly and Hynes, EMBO J. (1985) 4: 475479; EP 244,234; and WO 91/00357.

[0113] Expression of heterologous genes in insects can be accomplished as described in U.S. Pat. No. 4,745,051; Friesen et al. (1986) “The Regulation of Baculovirus Gene Expression” in: THE MOLECULAR BIOLOGY OF BACULOVIRUSES (W. Doerfler, ed.); EP 127,839; EP 155,476; Vlak et al., J. Gen. Virol. (1988) 69: 765-776; Miller et al., Ann. Rev. Microbiol. (1988) 42: 177; Carbonell et al., Gene (1988) 73: 409; Maeda et al., Nature (1985) 315:. 592-594; Lebacq-Verheyden et al., Mol. Cell Biol. (1988) 8: 3129; Smith et al., Proc. Natl. Acad. Sci. USA (1985) 82: 8404; Miyajima et al., Gene (1987) 58: 273; and Martin et al., DNA (1988) 7:99. Numerous baculoviral strains and variants and corresponding permissive insect host cells from hosts are described in Luckow et al., Bio/Technology (1988) 6:47-55, Miller et al., in GENERIC ENGINEERING (Setlow, J. K. et al. eds.), Vol. 8 (Plenum Publishing, 1986), pp. 277-279; and Maeda et al., Nature, (1985) 315: 592-594.

[0114] Mammalian expression can be accomplished as described in Dijkema et al., EMBO J. (1985) 4: 761; Gormanetal., Proc. Natl. Acad. Sci. USA (1982b) 79: 6777; Boshart et al., Cell (1985) 41: 521; and U.S. Pat. No. 4,399,216. Other features of mammalian expression can be facilitated as described in Ham and Wallace, Meth Enz. (1979) 58: 44; Barnes and Sato, Anal. Biochem. (1980) 102: 255; U.S. Pat. No. 4,767,704; U.S. Pat. No. 4,657,866; U.S. Pat. No. 4,927,762; U.S. Pat. No. 4,560,655; WO 90/103430, WO 87/00195, and U.S. RE 30,985.

[0115] Expression constructs can be introduced into host cells using any technique known in the art. These techniques include transferrin-polycation-mediated DNA transfer, transfection with naked or encapsulated nucleic acids, liposome-mediated cellular fusion, intracellular transportation of DNA-coated latex beads, protoplast fusion, viral infection, electroporation, “gene gun,” and calcium phosphate-mediated transfection.

[0116] Expression of an endogenous gene encoding a protein of the invention can also be manipulated by introducing by homologous recombination a DNA construct comprising a transcription unit in frame with the endogenous gene, to form a homologously recombinant cell comprising the transcription unit. The transcription unit comprises a targeting sequence, a regulatory sequence, an exon, and an unpaired splice donor site. The new transcription unit can be used to turn the endogenous gene on or off as desired. This method of affecting endogenous gene expression is taught in U.S. Pat. No. 5,641,670.

[0117] The targeting sequence is a segment of at least 10, 12, 15, 20, or 50 contiguous nucleotides selected from the nucleotide sequences shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29. The transcription unit is located upstream to a coding sequence of the endogenous gene. The exogenous regulatory sequence directs transcription of the coding sequence of the endogenous gene.

Functional Assays

[0118] A protein of the invention can exhibit cytokine, cell proliferation (either inducing or inhibiting), or cell differentiation (either inducing or inhibiting) activity, or can induce production of other cytokines in certain cell populations. Many protein factors discovered to date, including all known cytokines, have exhibited activity in one or more factor-dependent cell proliferation assays; hence, the assays serve as a convenient confirmation of cytokine activity. The activity of a protein of the invention can be evidenced by any one of a number of routine factor-dependent cell proliferation assays for cell lines including, 32D (a mouse IL-3-dependent lymphoblast cell line, ATCC No. CRL-11346), DA2, DA1G, T10 (a human myeloma cell line, ATCC No. CRL-9068), B9, B9/11, BaF3, MC9/G, M+(preB M+), 2E8 (a mouse IL-7-dependent Lymphoblast cell line, ATCC No. TIB-239), RB5, DA1, 123, T1165, HT2 (a mouse lymphoma cell line, ATCC No. CRL-8629), CTLL2, TF-I (a human IL-5-unresponsive Lymphoblast cell line, ATCC No. CRL-2003), Mo7e, and CMK.

[0119] Assays for T-cell or thymocyte proliferation include those described in Current Protocols in Immunology, Coligan et al., eds., Greene Publishing Associates and Wiley-Interscience (particularly chapter 3, In Vitro Assays for Mouse Lymphocyte Function 3.1-3.19; and chapter 7, Immunologic Studies in Humans); Takai et al., J. Immunol. 137:3494-3500, 1986; Bertagnolli et al., J. Immunol. 145:1706-1712, 1990; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Bertagnolli, et al., J Immunol. 149:3778-3783, 1992; and Bowman et al., J. Immunol. 152:1756-1761, 1994.

[0120] Assays for cytokine production and/or proliferation of spleen cells, lymph node cells, or thymocytes include those described in Kruisbeek and Shevach, Polyclonal T Cell Stimulation, in Current Protocols in Immunology, vol. I, pp. 3.12.1-3.12.14, and Schreiber, Measurement of Mouse and Human Interleukin Gamma, in Current Protocols in Immunology vol. 1, pp. 6.8.1-6.8.8.

[0121] Assays for proliferation and differentiation of hematopoietic and lymphopoietic cells include those described in Bottomly, Measurement of Human and Murine Interleukin 2 and Interleukin 4, in Current Protocols in Immunology vol. 1, pp. 6.3.1-6.3.12; deVries et al., J Exp. Med. 173: 1205-1211, 1991; Moreau et al., Nature 336:690-692, 1988; Greenberger et al., Proc. Natl. Acad. Sci. U.S.A. 80:2931-2938, 1983; Nordan, R., Measurement of mouse and human interleukin 6, in Current Protocols in Immunology vol. 1, pp. 6.6.1-6.6.5; Smith et al., Proc. Natl. Acad. Sci. U.S.A. 83:1857-1861, 1986; Bennett et al., Measurement of Human Interleukin 11, in Current Protocols in Immunology vol. 1, pp. 6.15.1; Ciarletta et al., Measurement of mouse and human Interleukin 9, in Current Protocols in Immunology vol. 1, p. 6.13.1.

[0122] Assays for T cell clone responses to antigens (which will identify, among others, proteins that affect APC-T cell interactions as well as direct T cell effects by measuring proliferation and cytokine production) include those described in Current Protocols in Immunology especially chapters 3 (In Vitro Assays for Mouse Lymphocyte Function), chapter 6 (Cytokines and Their Cellular Receptors), and chapter 7 (Immunologic Studies in Humans); Weinberger et al., Proc. Natl. Acad. Sci. USA 77:6091-6095, 1980; Weinberger et al., Eur. J Immun. 11:405-411, 1981; Takai et al., J Immunol. 137:3494-3500, 1986; and Takai et al., J: Immunol. 140:508-512, 1988.

[0123] Assays for tissue generation activity include those described for bone, cartilage, and tendon in WO 95/16035, for neuronal tissue in WO 95/05846, and for skin and endothelial tissue in WO 91/07491. Assays for wound healing activity include, for example, those described in Winter, Epidermal Wound Healing, polypeptides 71-112 (Maibach and Rovee, eds.), Year Book Medical Publishers, Inc., Chicago, and Eaglstein and Mertz, J. Invest. Dermatol 71:382-84 (1978).

[0124] A protein of the present invention can also demonstrate activity as a receptor, receptor ligand, or inhibitor or agonist of a receptor/ligand interaction. Examples of such receptors and ligands include cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved in cell-cell interactions and their ligands, including cellular adhesion molecules such as selecting, integrins, and their ligands, and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses. Receptors and ligands are also useful for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. A protein of the invention, including fragments of receptors and ligands, can itself be useful as an inhibitor of receptor/ligand interactions.

[0125] Suitable assays for receptor-ligand activity include those described in Current Protocols in Immunology, chapter 7.28, Measurement of Cellular Adhesion Under Static Conditions, pages 7.28.1-7.28.22, Takai et al., Proc. Natl. Acad. Sci. USA 84:6864-6868, 1987; Bierer et al., J. Exp. Med. 168:1145-1156, 1988; Rosenstein et al., J. Exp. Med. 169:149-160 1989; Stoltenborg et al., J. Immunol. Methods 175:59-68, 1994; Stittetal., Cell 80:661-670, 1995.

[0126] Suitable assays for proliferation and differentiation of various hematopoietic lines are cited above. Assays for embryonic stem cell differentiation which can identify proteins which influence embryonic hematopoiesis include those described in Johansson et al. Cellular Biology 15:141-151, 1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; and McClanahan et al., Blood 81:2903-2915, 1993.

[0127] Assays for stem cell survival and differentiation include those described in Freshney, Methylcellulose colony forming assays, in Culture of Hematopoietic Cells, Freshney et al. eds., pp. 265-268, Wiley-Liss, Inc., New York, N.Y. 1994; Hirayamaet all, Proc. Natl. Acad. Sci. USA 89:5907-5911, 1992; McNiece and Briddell, Primitive hematopoietic colony forming cells with high proliferative potential, in Culture of Hematopoietic Cells, pp. 23-39; Neben et al., Experimental Hematology 22:353-359, 1994; Ploemacher, Cobblestone area forming cell assay, in Culture of Hematopoietic Cells, pp. 1-21; Spooncer et al., Long term bone marrow cultures in the presence of stromal cells, in Culture of Hematopoietic Cells, pp. 163-179; Sutherland, Long term culture initiating cell assay, in Culture of Hematopoietic Cells, pp. 139-162. Such assays can be used to identify proteins which regulate lympho-hematopoiesis.

Therapeutic Uses of Secreted Proteins and Polynucleotides Molecules

[0128] A protein of the present invention can be used to support colony forming cells or factor-dependent cell lines, to regulate hematopoiesis, and to treat myeloid or lymphoid cell deficiencies. The protein can be used, either alone or in combination with other cytokines, to support the growth and proliferation of erythroid progenitor cells. Proteins of the invention can also be used to treat various anemias, in conjunction with irradiation or chemotherapy to stimulate the production of erythroid precursors or erythroid cells.

[0129] A protein of the invention which has CSF activity can be used to support the growth and proliferation of myeloid cells, such as granulocytes, monocytes, or macrophages. Proteins with such activity can be used, for example, in conjunction with chemotherapy to prevent or treat myelo-suppression. Proteins of the invention can also be used to support the growth and proliferation of megakaryocytes and platelets, thereby allowing prevention or treatment of platelet disorders such as thrombocytopenia. Proteins with such activity can be used to support the growth and proliferation of hematopoietic stem cells, either in place of or in conjunction with platelet transfusions. Proteins of the invention can be used to treat stem cell disorders, such as aplastic anemia and paroxysmal nocturnal hemoglobinuria, or to repopulate the stem cell compartment after irradiation or chemotherapy, either in vivo or ex vivo. For example, a protein of the invention can be used in conjunction with homologous or heterologous bone marrow transplantation or peripheral progenitor cell transplantation.

[0130] Proteins of the invention, or fragments thereof, can be useful for treatment and diagnosis of a variety of conditions in which the rate of cell growth, and cell-cell interactions, are disrupted. Such conditions include cancer.

[0131] A protein of the invention also can have utility in compositions used for growth or differentiation of bone, cartilage, tendon, ligament, or nerve tissue, as well as for wound healing and tissue repair and replacement, and in the treatment of burns, incisions, and ulcers.

[0132] Proteins of the present invention can induce cartilage and/or bone growth in circumstances where bone is not normally formed and thus have an application in healing bone fractures and cartilage damage or defects in humans and other animals. A preparation employing a protein of the invention can have prophylactic use in closed as well as open fracture reduction and also in the improved fixation of artificial joints. De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma- or surgery-induced craniofacial defects and also is useful in cosmetic plastic surgery.

[0133] A protein of this invention can also be used in the treatment of periodontal disease and in other tooth repair processes. Such agents can provide an environment to attract bone-forming cells, stimulate growth of bone-forming cells, or induce differentiation of progenitors of bone-forming cells. A protein of the invention can be used to treat osteoporosis or osteoarthritis, for example, through stimulation of bone and/or cartilage repair or by blocking inflammation. Mechanisms of destroying tissue mediated by inflammatory processes, such as collagenase or osteoclast activity, can also be inhibited.

[0134] Tendon or ligament formation can also be influenced by a protein of the invention. A protein of the invention which induces tendon/ligament-like tissue or other tissue formation in circumstances where such tissue is not normally formed can be used to heal tendon or ligament tears, deformities, and other tendon or ligament defects in humans and other animals. A preparation employing a tendon/ligament-like tissue inducing protein can be used to prevent damage to tendon or ligament tissue, as well as in the improved fixation of tendon or ligament to bone or other tissues, and to repair defects to tendon or ligament tissue. De novo tendon/ligament-like tissue formation induced by a composition of the invention contributes to the repair of congenital, trauma-induced, or other tendon or ligament defects of other origin and can also be used in cosmetic plastic surgery, for attachment or repair of tendons or ligaments.

[0135] A protein of the invention can also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders. More specifically, a protein can be used in the treatment of diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome. Other conditions which can be treated in accordance with the invention include mechanical and traumatic disorders, such as spinal cord disorders and head trauma, and cerebrovascular diseases, such as stroke. Peripheral neuropathies resulting from chemotherapy or other medical therapies can be treated using a protein of the invention.

[0136] Proteins of the invention can also be used to promote better or faster closure of non-healing wounds, including pressure ulcers, ulcers associated with vascular insufficiency, or surgical and traumatic wounds.

[0137] A protein of the invention can also affect generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal, or cardiac), and vascular (including vascular endothelium) tissue, or for promoting the growth of cells of which such tissues are comprised. Part of the desired effects can be by inhibition or modulation of fibrotic scarring to allow normal tissue to regenerate. A protein of the invention can also exhibit angiogenic activity.

[0138] A protein of the present invention can be useful for gut protection or regeneration, and for treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokine damage. A protein of the invention can also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells or for inhibiting the growth of tissues described above.

[0139] Secreted proteins and polynucleotides of the invention can be used in a composition. Compositions of the invention relate to isolated (purified) polypeptides and polynucleotides. These compositions are substantially free of other human proteins or human polynucleotides. A composition containing A is “substantially free of” B when at least 85% by weight of the total A+B in the composition is A. Preferably, A comprises at least about 90% by weight of the total of A+B in the composition, more preferably at least about 96% or even 99% by weight.

[0140] A protein of the invention can be used in a pharmaceutical composition. Compositions comprising proteins or polynucleotides of the invention have therapeutic applications, both for human patients and veterinary patients, such as domestic animals and thoroughbred horses. Such compositions can optionally include a pharmaceutically acceptable carrier. In addition to protein and carrier, such a composition can also contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. Characteristics of a carrier will depend on the route of administration. Compositions of the invention can also contain cytokines, lymphokines, or other hematopoietic factors such as M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN, TNFO, TNF1, TNF2, G-CSF, Meg-CSF, thrombopoietin, stem cell factor, erythropoietin, or growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factors (TGF-α and TGF-β), or insulin-like growth factor (IGF).

[0141] A pharmaceutical composition can also contain other agents which either enhance the activity of the protein or complement its activity or use in treatment. Such additional factors and/or agents can be included in the pharmaceutical composition to produce a synergistic effect with a protein of the invention or to minimize side effects. Conversely, a protein of the invention can be included in formulations of a particular factor, such as a cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent to minimize side effects of the factor.

[0142] A protein of the present invention can be active in multimers (e.g., heterodimers or homodimers) or complexes with itself or other proteins, and compositions of the invention can comprise a protein of the invention in such a multimeric or complexed form. For example, a composition of the invention can be in the form of a complex of a protein or proteins of the invention together with protein or peptide antigens. The protein or peptide antigen will deliver a stimulatory signal to both B and T Lymphocytes. B Lymphocytes will respond to antigen through their surface immunoglobulin receptor. T Lymphocytes will respond to antigen through the T cell receptor (TCR) following presentation of the antigen by MHC proteins. MHC proteins and structurally related proteins, including those encoded by class I and class II MHC genes on host cells, can present the peptide antigen(s) to T Lymphocytes. Antigen components could also be supplied as purified MUC-peptide complexes alone or, with co-stimulatory molecules which can directly signal T cells. Alternatively, antibodies able to bind surface immunoglobulin and other molecules on B cells, as well as antibodies able to bind the TCR and other molecules on T cells, can be combined with a composition of the invention.

[0143] A composition of the invention can be in the form of a liposome in which a protein of the invention is combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids, which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Pat. No. 4,235,871, U.S. Pat. No. 4,501,728, U.S. Pat. No. 4,837,028, and U.S. Pat. No. 4,737,323.

[0144] A therapeutically effective amount of a protein of the invention is administered to a mammal having a condition to be treated. The amount of protein which is therapeutically effective is that amount of protein which is sufficient to treat, heal, prevent, or ameliorate the condition, or to increase the rate of such treatment. Proteins of the invention can be administered either alone or in combination with other therapeutic agents, such as cytokines, lymphokines, or other hematopoietic factors. Other therapeutic agents can be administered simultaneously or sequentially with proteins of the invention, as determined by the attending physician.

[0145] Compositions of the invention can be inhaled, ingested, applied topically, or administered by cutaneous, subcutaneous, intraperitoneal, parenteral or intravenous injection. When a therapeutically effective amount of protein of the present invention is administered orally, protein of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention can additionally contain a solid carrier such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5-95%, 25-90%, 30-80%, 40-75%, or 50% protein of the invention by weight. When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils can be added.

[0146] The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5-90%, 1-80%, 5-75%, 10-65%, 20-50%, 10-50%, or 25-40% by weight of protein of the invention.

[0147] When a therapeutically effective amount of protein of the present invention is administered by intravenous, cutaneous, or subcutaneous injection, a pyrogen-free, parenterally acceptable aqueous solution of the protein is preferred. The skilled artisan can readily prepare an acceptable protein solution with suitable pH, isotonicity, and stability. A solution of the composition for intravenous, cutaneous, or subcutaneous injection should also contain an isotonic vehicle, such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicles as are known in the art. Stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art can also be added to the composition.

[0148] The amount of protein of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of protein of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of protein of the present invention and observe the patient's response. Larger doses of protein of the present invention can be administered until the optimal therapeutic-effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.01 μg to about 100 mg (preferably about 0.1 μg to about 10 mg, more preferably about 0.1 μg to about 1 mg) of protein of the present invention per kg body weight.

[0149] Duration of intravenous therapy using a composition of the invention will vary, depending on the severity of the disease being treated and the condition and potential idiosyncratic response of each individual patient. It is contemplated that the duration of each application of a composition of the invention will be in the range of 12 to 24 hours of continuous intravenous administration. Ultimately, the attending physician will decide on the appropriate duration of intravenous therapy.

[0150] A composition of the invention which is useful for bone, cartilage, tendon or ligament regeneration can be administered topically, systematically, or locally in an implant or device. Encapsulation or injection in a viscous form for delivery to the site of bone, cartilage or tissue damage is also possible. Topical administration can be suitable for wound healing and tissue repair. Optionally, therapeutic agents other than a protein of the invention can be included in the composition, as described above.

[0151] For affecting bone or cartilage formation, a composition of the invention would include a matrix capable of delivering the composition to the site of bone or cartilage damage and for providing a structure for the developing bone and cartilage. Optimally, the matrix would be capable of resorption into the body. Matrices can be formed of materials presently in use for other implanted medical applications, the choice of material being based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance, and interface properties. Suitable biodegradable matrix materials include chemically defined calcium sulfate, tricalciumphosphate, hydroxyapatite, polylactic acid, polyglycolic acid, polyanhydride, bone or dermal collagen, pure proteins, and extracellular matrix components. Suitable nonbiodegradable and chemically defined matrix materials include sintered hydroxyapatite, bioglass, aluminates, or other ceramics. Individual matrix components can be modified, for example, to affect pore size, particle size, particle shape, and biodegradability. Combinations of materials can be used, as is known in the art.

[0152] Sequestering agents, such as carboxymethyl cellulose or an autologous blood clot, can be employed to prevent protein compositions from dissociating from the matrix. Sequestering agents include cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, and carboxymethylcellulose, the most preferred being cationic salts of carboxymethylcellulose (CMC). Other preferred sequestering agents include hyaluronic acid, sodium alginate, polyethylene glycol, polyoxyethylene oxide, carboxyvinyl polymer and polyvinyl alcohol. The amount of sequestering agent is based on total formulation weight, such as 0.5-20% or 1-10%, and should be an amount of sequestering agent which prevents desorbtion of the protein from the polymer matrix but which permits progenitor cells to infiltrate the matrix, so that the protein can assist the osteogenic activity of the progenitor cells.

[0153] Compositions comprising proteins of the invention can provide an environment which will attract tendon- or ligament-forming cells, stimulate growth of tendon- or ligament-forming cells, induce differentiation of progenitors of tendon-or ligament-forming cells, or induce growth of tendon/ligament cells or progenitors ex vivo. Such cells can then be returned to the body to effect tissue repair. Compositions of the invention can also be used to treat tendonitis, carpal tunnel syndrome, and other tendon or ligament defects. Such compositions can optionally include an appropriate matrix and/or sequestering agent as a pharmaceutically acceptable carrier, as is well known in the art.

[0154] The dosage regimen of a protein-containing pharmaceutical composition to be used in tissue regeneration will be determined by the attending physician considering various factors which modify the action of the proteins, e.g. amount of tissue weight desired to be formed, the site of damage, the condition of the damaged tissue, the size of a wound, type of damaged tissue (e.g., bone), the patient's age, sex, and diet, the severity of any infection, time of administration, and other clinical factors. The dosage can vary with the type of matrix used in the reconstitution and whether other therapeutic agents, such as growth factors, are included. Progress of the treatment can be monitored by periodic assessment of tissue/bone growth and/or repair, for example, using X-rays, histomorphometric determinations, or tetracycline labeling.

[0155] Polynucleotides of the invention can also be used for gene therapy. Polynucleotides can be introduced either in vivo or ex vivo into cells for expression in a mammalian subject. Cells can be cultured ex vivo in the presence of proteins of the invention in order to produce a desired effect on or activity in such cells. Treated cells can then be introduced in vivo for therapeutic purposes, as is known in the art. Polynucleotides of the invention can be administered by known methods of introducing polynucleotides into a cell or organism (including in the form of viral vectors or naked DNA).

[0156] Polynucleotides of the invention can also be delivered to subjects for the purpose of screening test compounds for those which are useful for enhancing transfer of polynucleotides of the invention to a cell or for enhancing subsequent biological effects of the polynucleotides within the cell. Such biological effects include hybridization to complementary mRNA and inhibition of its translation, expression of the polynucleotide to form mRNA and/or protein, and replication and integration of the polynucleotide.

[0157] Test compounds which can be screened include any substances, whether natural products or synthetic, which can be administered to the subject. Libraries or mixtures of compounds can be tested. The compounds or substances can be those for which a pharmaceutical effect is previously known or unknown. The compounds or substances can be delivered before, after, or concomitantly with the polynucleotides. They can be administered separately or in admixture with the polynucleotides.

[0158] Integration of delivered polynucleotides can be monitored by any means known in the art. For example, Southern blotting of the delivered polynucleotides can be performed. A change in the size of the fragments of the delivered polynucleotides indicates integration. Replication of the delivered polynucleotides can be monitored inter alia by detecting incorporation of labeled nucleotides combined with hybridization to a specific nucleotide probe. Expression of a polynucleotide of the invention can be monitored by detecting production of mRNA which hybridizes to the delivered polynucleotide or by detecting protein. Proteins of the invention can be detected immunologically. Thus, delivery of polynucleotides of the invention according to the present invention provides an excellent system for screening test compounds for their ability to enhance delivery, integration, hybridization, expression, replication or integration in an animal, preferably a mammal, more preferably a human.

Research Uses of the Polynucleotides and Secreted Proteins

[0159] Polynucleotides of the invention can be used for a variety of research purposes. Any or all of these research utilities are capable of being developed into reagent grade or kit format for commercialization as research products. For example, polynucleotides can be used to express recombinant protein for analysis, characterization, or therapeutic use. Polynucleotides can be used as markers for tissues in which the corresponding protein is preferentially expressed, either constitutively or at a particular stage of tissue differentiation or development or in disease states. Polynucleotides can also be used as molecular weight markers on Southern gels or, when labeled, for example, with a fluorescent tag or a radiolabel, polynucleotides can be used as chromosome markers, to identify chromosomes for gene mapping.

[0160] Potential genetic disorders can be identified by comparing the sequences of wild-type polynucleotides of the invention with endogenous nucleotide sequences in patients. Polynucleotides of the invention can also be used as probes for the discovery of novel, related DNA sequences, to derive PCR primers for genetic fingerprinting, as probes to “subtract-out” known sequences in the process of discovering other novel polynucleotides, for selecting and making oligomers for attachment to a gene chip or other support, to raise anti-protein antibodies using DNA immunization techniques, and as immunogens, to raise anti-DNA antibodies or to elicit another immune response.

[0161] Where the polynucleotide encodes a protein which binds or potentially binds to another protein, such as in a receptor-ligand interaction, the polynucleotide can also be used in interaction trap assays, such as the yeast two-hybrid assay, to identify polynucleotides encoding the protein with which binding occurs or to identify inhibitors of the binding interaction, for example in drug screening assays.

[0162] Proteins of the invention can similarly be used in assays to determine biological activity, including use in a panel of multiple proteins for high-throughput screening, to raise antibodies or to elicit another immune response, as a reagent in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids, as markers for tissues in which the protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state), and to identify related receptors or ligands. Where the protein binds or potentially binds to another protein such as, for example, in a receptor-ligand interaction, the protein can be used to identify the other protein with which binding occurs or to identify inhibitors of the binding interaction. Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.

EXAMPLES Example 1 Identification of Trans-Membrane Human Proteins

[0163] A cDNA clone designated ch1572 was isolated from a fetal liver library. The cDNA contained a 1994 base pair insert (SEQ ID NO:21) encoding a 585 amino acid protein (SEQ ID NO:22). The amino acid sequence contained a hydrophobic region of amino acids at positions 14 to 33, followed by a potential signal peptidase cleavage site between amino acids 33 and 34.

[0164] Five potential N-linked glycoprotein sites were identified, at amino acids 89, 106, 189, 220 and 315 of SEQ ID NO:22. When the protein was translated in the presence of endoplasmic reticulum membranes, the molecular weight increased in a manner consistent with glycosylation.

[0165] A cDNA clone designated ch1569 was isolated from a fetal liver library. The cDNA contained a 1340 base pair insert (SEQ ID NO:23) encoding a 280 amino acid protein (SEQ ID NO:24). Hydrophobic regions were found at amino acids 1 to 20 and 180 to 206, and a potential signal peptidase cleavage site was located between amino acids 20 and 21. No potential glycosylation sites were found. Where the protein was translated in the presence of rough endoplasmic reticulum, decreased molecular weights was observed, consistent with removal of the signal peptide.

[0166] A cDNA clone designated ch1570 was isolated from a fetal liver library. The cDNA contained a 1011 base pair insert (SEQ ID NO:25) encoding a 286 amino acid protein (SEQ ID NO:26). Five hydrophobic stretches were found, at positions 27 to 53, 62 to 86, 96 to 118, 206 to 246, and 257 to 279. Potential glycosylation sites were found at positions 8, 130, 134, 145, and 151. When the protein was translated in the presence of endoplasmic reticulum, the molecular weight increased, consistent with glycosylation.

[0167] A cDNA clone designated ch1529 was isolated from a fetal liver library. The cDNA contained a 2027 base pair insert (SEQ ID NO:27) encoding a 340 amino acid protein. Five hydrophobic stretches were found, at amino acid positions 19 to 44, 144 to 164, 180 to 223, 231 to 255, and260 to 280.

[0168] Potential N-linked glycosylation sites were found at positions 39, 56, 62, 102 and 107. When the protein was translated in the presence of rough endoplasmic reticulum, the molecular weight increased, consistent with glycosylation of the protein.

[0169] A cDNA clone designated ch1515 was isolated from a fetal liver library. The cDNA contained a 2390 base pair insert (SEQ ID NO:29) encoding a 347 amino acid protein (SEQ ID NO:30). The protein contained a 30 amino acid hydrophobic region between amino acids 55 to 85, which could act as a signal peptide and/or a transmembrane domain.

[0170] Potential N-linked glycosylation sites were found at positions 147, 155 and 237. When the protein was translated in the presence of rough endoplasmic reticulum, an increase in molecular weight was observed, consistent with glycosylation.

[0171] Further objects, features, and advantages of the present invention will readily occur to the skilled artisan provided with the disclosure above. The complete contents of all references cited in this disclosure are expressly incorporated herein by reference.

1 30 1 1313 DNA Homo sapiens CDS (163)...(1137) 1 gaattcggca cgaggatttc cacccagaag acagagaagg agccagtggt catggaatgg 60 gctggggtca aagactgggt gcctgggagc tgaggcagcc accgtttcag cctggccagc 120 cctctggacc ccgaggttgg accctactgt gacacaccta cc atg cgg aca ctc 174 Met Arg Thr Leu 1 ttc aac ctc ctc tgg ctt gcc ctg gcc tgc agc cct gtt cac act acc 222 Phe Asn Leu Leu Trp Leu Ala Leu Ala Cys Ser Pro Val His Thr Thr 5 10 15 20 ctg tca aag tca gat gcc aaa aaa gcc gcc tca aag acg ctg ctg gag 270 Leu Ser Lys Ser Asp Ala Lys Lys Ala Ala Ser Lys Thr Leu Leu Glu 25 30 35 aag agt cag ttt tca gat aag ccg gtg caa gac cgg ggt ttg gtg gtg 318 Lys Ser Gln Phe Ser Asp Lys Pro Val Gln Asp Arg Gly Leu Val Val 40 45 50 acg gac ctc aaa gct gag agt gtg gtt ctt gag cat cgc agc tac tgc 366 Thr Asp Leu Lys Ala Glu Ser Val Val Leu Glu His Arg Ser Tyr Cys 55 60 65 tcg gca aag gcc cgg gac aga cac ttt gct ggg gat gta ctg ggc tat 414 Ser Ala Lys Ala Arg Asp Arg His Phe Ala Gly Asp Val Leu Gly Tyr 70 75 80 gtc act cca tgg aac agc cat ggc tac gat gtc acc aag gtc ttt ggg 462 Val Thr Pro Trp Asn Ser His Gly Tyr Asp Val Thr Lys Val Phe Gly 85 90 95 100 agc aag ttc aca cag atc tca ccc gtc tgg ctg cag ctg aag aga cgt 510 Ser Lys Phe Thr Gln Ile Ser Pro Val Trp Leu Gln Leu Lys Arg Arg 105 110 115 ggc cgt gag atg ttt gag gtc acg ggc ctc cac gac gtg gac caa ggg 558 Gly Arg Glu Met Phe Glu Val Thr Gly Leu His Asp Val Asp Gln Gly 120 125 130 tgg atg cga gct gtc agg aag cat gcc aag ggc ctg cac ata gtg cct 606 Trp Met Arg Ala Val Arg Lys His Ala Lys Gly Leu His Ile Val Pro 135 140 145 cgg ctc ctg ttt gag gac tgg act tac gat gat ttc cgg aac gtc tta 654 Arg Leu Leu Phe Glu Asp Trp Thr Tyr Asp Asp Phe Arg Asn Val Leu 150 155 160 gac agt gag gat gag ata gag gag ctg agc aag acc gtg gtc cag gtg 702 Asp Ser Glu Asp Glu Ile Glu Glu Leu Ser Lys Thr Val Val Gln Val 165 170 175 180 gca aag aac cag cat ttc gat ggc ttc gtg gtg gag gtc tgg aac cag 750 Ala Lys Asn Gln His Phe Asp Gly Phe Val Val Glu Val Trp Asn Gln 185 190 195 ctg cta agc cag aag cgc gtg ggc ctc atc cac atg ctc acc cac ttg 798 Leu Leu Ser Gln Lys Arg Val Gly Leu Ile His Met Leu Thr His Leu 200 205 210 gcc gag gct ctg cac cag gcc cgg ctg ctg gcc ctc ctg gtc atc ccg 846 Ala Glu Ala Leu His Gln Ala Arg Leu Leu Ala Leu Leu Val Ile Pro 215 220 225 cct gcc atc acc ccc ggg acc gac cag ctg ggc atg ttc acg cac aag 894 Pro Ala Ile Thr Pro Gly Thr Asp Gln Leu Gly Met Phe Thr His Lys 230 235 240 gag ttt gag cag ctg gcc ccc gtg ctg gat ggt ttc agc ctc atg acc 942 Glu Phe Glu Gln Leu Ala Pro Val Leu Asp Gly Phe Ser Leu Met Thr 245 250 255 260 tac gac tac tct aca gcg cat cag cct ggc cct aat gca ccc ctg tcc 990 Tyr Asp Tyr Ser Thr Ala His Gln Pro Gly Pro Asn Ala Pro Leu Ser 265 270 275 tgg gtt cga gcc tgc gtc cag gtc ctg gac ccg aag tcc aag tgg cga 1038 Trp Val Arg Ala Cys Val Gln Val Leu Asp Pro Lys Ser Lys Trp Arg 280 285 290 agc aaa atc ctc ctg ggg ctc aac ttc tat ggt atg gac tac gcg acc 1086 Ser Lys Ile Leu Leu Gly Leu Asn Phe Tyr Gly Met Asp Tyr Ala Thr 295 300 305 tcc aag gat gcc cgt gag cct gtt gtc ggg gcc agt gtt cat gga gcc 1134 Ser Lys Asp Ala Arg Glu Pro Val Val Gly Ala Ser Val His Gly Ala 310 315 320 tct tgagtctgca ttcgtactct tagcaaactt ggaaaatttg aggccaaatt 1187 Ser 325 cttcaaatat tttttctgtt tcttctcttc tgtcttctcg tttggagacc acaaacacta 1247 gatccattga atttgtccca cagctcacga atacaccttt taccttttaa aaaaaaaaaa 1307 aaaaaa 1313 2 325 PRT Homo sapiens 2 Met Arg Thr Leu Phe Asn Leu Leu Trp Leu Ala Leu Ala Cys Ser Pro 1 5 10 15 Val His Thr Thr Leu Ser Lys Ser Asp Ala Lys Lys Ala Ala Ser Lys 20 25 30 Thr Leu Leu Glu Lys Ser Gln Phe Ser Asp Lys Pro Val Gln Asp Arg 35 40 45 Gly Leu Val Val Thr Asp Leu Lys Ala Glu Ser Val Val Leu Glu His 50 55 60 Arg Ser Tyr Cys Ser Ala Lys Ala Arg Asp Arg His Phe Ala Gly Asp 65 70 75 80 Val Leu Gly Tyr Val Thr Pro Trp Asn Ser His Gly Tyr Asp Val Thr 85 90 95 Lys Val Phe Gly Ser Lys Phe Thr Gln Ile Ser Pro Val Trp Leu Gln 100 105 110 Leu Lys Arg Arg Gly Arg Glu Met Phe Glu Val Thr Gly Leu His Asp 115 120 125 Val Asp Gln Gly Trp Met Arg Ala Val Arg Lys His Ala Lys Gly Leu 130 135 140 His Ile Val Pro Arg Leu Leu Phe Glu Asp Trp Thr Tyr Asp Asp Phe 145 150 155 160 Arg Asn Val Leu Asp Ser Glu Asp Glu Ile Glu Glu Leu Ser Lys Thr 165 170 175 Val Val Gln Val Ala Lys Asn Gln His Phe Asp Gly Phe Val Val Glu 180 185 190 Val Trp Asn Gln Leu Leu Ser Gln Lys Arg Val Gly Leu Ile His Met 195 200 205 Leu Thr His Leu Ala Glu Ala Leu His Gln Ala Arg Leu Leu Ala Leu 210 215 220 Leu Val Ile Pro Pro Ala Ile Thr Pro Gly Thr Asp Gln Leu Gly Met 225 230 235 240 Phe Thr His Lys Glu Phe Glu Gln Leu Ala Pro Val Leu Asp Gly Phe 245 250 255 Ser Leu Met Thr Tyr Asp Tyr Ser Thr Ala His Gln Pro Gly Pro Asn 260 265 270 Ala Pro Leu Ser Trp Val Arg Ala Cys Val Gln Val Leu Asp Pro Lys 275 280 285 Ser Lys Trp Arg Ser Lys Ile Leu Leu Gly Leu Asn Phe Tyr Gly Met 290 295 300 Asp Tyr Ala Thr Ser Lys Asp Ala Arg Glu Pro Val Val Gly Ala Ser 305 310 315 320 Val His Gly Ala Ser 325 3 1941 DNA Homo sapiens CDS (262)...(1566) 3 gaattcggca cgaggccgcc tgggccccgc cgagcggagc tagcgccgcg cgcagagcac 60 acgctcgcgc tccagctccc ctcctgcgcg gttcatgact gtgtcccctg accgcagcct 120 ctgcgagccc ccgccgcagg accacggccc gctccccgcc gccgcgaggg ccccgagcga 180 aggaaggaag ggaggcgcgc tgtgcgcccc gcggagcccg cgaaccccgc tcgctgccgg 240 ctgcccagcc tggctggcac c atg ctg ccc gcg cgc tgc gcc cgc ctg ctc 291 Met Leu Pro Ala Arg Cys Ala Arg Leu Leu 1 5 10 acg ccc cac ttg ctg ctg gtg ttg gtg cag ctg tcc cct gct cgc ggc 339 Thr Pro His Leu Leu Leu Val Leu Val Gln Leu Ser Pro Ala Arg Gly 15 20 25 cac cgc acc aca ggc ccc agg ttt cta ata agt gac cgt gac cca cag 387 His Arg Thr Thr Gly Pro Arg Phe Leu Ile Ser Asp Arg Asp Pro Gln 30 35 40 tgc aac ctc cac tgc tcc agg act caa ccc aaa ccc atc tgt gcc tct 435 Cys Asn Leu His Cys Ser Arg Thr Gln Pro Lys Pro Ile Cys Ala Ser 45 50 55 gat ggc agg tcc tac gag tcc atg tgt gag tac cag cga gcc aag tgc 483 Asp Gly Arg Ser Tyr Glu Ser Met Cys Glu Tyr Gln Arg Ala Lys Cys 60 65 70 cga gac ccg acc ctg ggc gtg gtg cat cga ggt aga tgc aaa gat gct 531 Arg Asp Pro Thr Leu Gly Val Val His Arg Gly Arg Cys Lys Asp Ala 75 80 85 90 ggc cag agc aag tgt cgc ctg gag cgg gct caa gcc ctg gag caa gcc 579 Gly Gln Ser Lys Cys Arg Leu Glu Arg Ala Gln Ala Leu Glu Gln Ala 95 100 105 aag aag cct cag gaa gct gtg ttt gtc cca gag tgt ggc gag gat ggc 627 Lys Lys Pro Gln Glu Ala Val Phe Val Pro Glu Cys Gly Glu Asp Gly 110 115 120 tcc ttt acc cag gtg cag tgc cat act tac act ggg tac tgc tgg tgt 675 Ser Phe Thr Gln Val Gln Cys His Thr Tyr Thr Gly Tyr Cys Trp Cys 125 130 135 gtc acc ccg gat ggg aag ccc atc agt ggc tct tct gtg cag aat aaa 723 Val Thr Pro Asp Gly Lys Pro Ile Ser Gly Ser Ser Val Gln Asn Lys 140 145 150 act cct gta tgt tca ggt tca gtc acc gac aag ccc ttg agc cag ggt 771 Thr Pro Val Cys Ser Gly Ser Val Thr Asp Lys Pro Leu Ser Gln Gly 155 160 165 170 aac tca gga agg aaa gat gac ggg tct aag ccg aca ccc acg atg gag 819 Asn Ser Gly Arg Lys Asp Asp Gly Ser Lys Pro Thr Pro Thr Met Glu 175 180 185 acc cag ccg gtg ttc gat gga gat gaa atc aca gcc cca act cta tgg 867 Thr Gln Pro Val Phe Asp Gly Asp Glu Ile Thr Ala Pro Thr Leu Trp 190 195 200 att aaa cac ttg gtg atc aag gac tcc aaa ctg aac aac acc aac ata 915 Ile Lys His Leu Val Ile Lys Asp Ser Lys Leu Asn Asn Thr Asn Ile 205 210 215 aga aat tca gag aaa gtc tat tcg tgt gac cag gag agg cag agt gcc 963 Arg Asn Ser Glu Lys Val Tyr Ser Cys Asp Gln Glu Arg Gln Ser Ala 220 225 230 ctg gaa gag gcc cag cag aat ccc cgt gag ggt att gtc atc cct gaa 1011 Leu Glu Glu Ala Gln Gln Asn Pro Arg Glu Gly Ile Val Ile Pro Glu 235 240 245 250 tgt gcc cct ggg gga ctc tat aag cca gtg caa tgc cac cag tcc act 1059 Cys Ala Pro Gly Gly Leu Tyr Lys Pro Val Gln Cys His Gln Ser Thr 255 260 265 ggc tac tgc tgg tgt gtg ctg gtg gac aca ggg cgc ccg ctg cct ggg 1107 Gly Tyr Cys Trp Cys Val Leu Val Asp Thr Gly Arg Pro Leu Pro Gly 270 275 280 acc tcc aca cgc tac gtg atg ccc agt tgt gag agc gac gcc agg gcc 1155 Thr Ser Thr Arg Tyr Val Met Pro Ser Cys Glu Ser Asp Ala Arg Ala 285 290 295 aag act aca gag gcg gat gac ccc ttc aag gac agg gag cta cca ggc 1203 Lys Thr Thr Glu Ala Asp Asp Pro Phe Lys Asp Arg Glu Leu Pro Gly 300 305 310 tgt cca gaa ggg aag aaa atg gag ttt atc acc agc cta ctg gat gct 1251 Cys Pro Glu Gly Lys Lys Met Glu Phe Ile Thr Ser Leu Leu Asp Ala 315 320 325 330 ctc acc act gac atg gtt cag gcc att aac tca gca gcg ccc act gga 1299 Leu Thr Thr Asp Met Val Gln Ala Ile Asn Ser Ala Ala Pro Thr Gly 335 340 345 ggt ggg agg ttc tca gag cca gac ccc agc cac acc ctg gag gag cgg 1347 Gly Gly Arg Phe Ser Glu Pro Asp Pro Ser His Thr Leu Glu Glu Arg 350 355 360 gta gtg cac tgg tat ttc agc cag ctg gac agc aat agc agc aac gac 1395 Val Val His Trp Tyr Phe Ser Gln Leu Asp Ser Asn Ser Ser Asn Asp 365 370 375 att aac aag cgg gag atg aag ccc ttc aag cgc tac gtg aag aag aaa 1443 Ile Asn Lys Arg Glu Met Lys Pro Phe Lys Arg Tyr Val Lys Lys Lys 380 385 390 gcc aag ccc aag gaa tgt gcc cgg cgt ttc acc gac tac tgt gac ctg 1491 Ala Lys Pro Lys Glu Cys Ala Arg Arg Phe Thr Asp Tyr Cys Asp Leu 395 400 405 410 aac aaa gac aag gtc att tca ctg cct gag ctg aag ggc tgc ctg ggt 1539 Asn Lys Asp Lys Val Ile Ser Leu Pro Glu Leu Lys Gly Cys Leu Gly 415 420 425 gtt agc aaa gaa gta gga cgc ctc gtc taaggagcag aaaacccaag 1586 Val Ser Lys Glu Val Gly Arg Leu Val 430 435 ggcaggtgga gagtccaggg aggcaggatg gatcaccaga cacctaacct tcagcgttgc 1646 ccatggccct gccacatccc gtgtaacata agtggtgccc accatgtttg cacttttaat 1706 aactcttact tgcgtgtttt gtttttggtt tcattttaaa acaccaatat ctaataccac 1766 agtgggaaaa ggaaagggaa gaaagacttt attctctctc ttattgtaag tttttggatc 1826 tgctactgac aacttttaga gggttttggg ggggtggggg agggtgttgt tggggctgag 1886 aagaaagaga tttatatgct gtatataaat atatatgtaa aaaaaaaaaa aaaaa 1941 4 435 PRT Homo sapiens 4 Met Leu Pro Ala Arg Cys Ala Arg Leu Leu Thr Pro His Leu Leu Leu 1 5 10 15 Val Leu Val Gln Leu Ser Pro Ala Arg Gly His Arg Thr Thr Gly Pro 20 25 30 Arg Phe Leu Ile Ser Asp Arg Asp Pro Gln Cys Asn Leu His Cys Ser 35 40 45 Arg Thr Gln Pro Lys Pro Ile Cys Ala Ser Asp Gly Arg Ser Tyr Glu 50 55 60 Ser Met Cys Glu Tyr Gln Arg Ala Lys Cys Arg Asp Pro Thr Leu Gly 65 70 75 80 Val Val His Arg Gly Arg Cys Lys Asp Ala Gly Gln Ser Lys Cys Arg 85 90 95 Leu Glu Arg Ala Gln Ala Leu Glu Gln Ala Lys Lys Pro Gln Glu Ala 100 105 110 Val Phe Val Pro Glu Cys Gly Glu Asp Gly Ser Phe Thr Gln Val Gln 115 120 125 Cys His Thr Tyr Thr Gly Tyr Cys Trp Cys Val Thr Pro Asp Gly Lys 130 135 140 Pro Ile Ser Gly Ser Ser Val Gln Asn Lys Thr Pro Val Cys Ser Gly 145 150 155 160 Ser Val Thr Asp Lys Pro Leu Ser Gln Gly Asn Ser Gly Arg Lys Asp 165 170 175 Asp Gly Ser Lys Pro Thr Pro Thr Met Glu Thr Gln Pro Val Phe Asp 180 185 190 Gly Asp Glu Ile Thr Ala Pro Thr Leu Trp Ile Lys His Leu Val Ile 195 200 205 Lys Asp Ser Lys Leu Asn Asn Thr Asn Ile Arg Asn Ser Glu Lys Val 210 215 220 Tyr Ser Cys Asp Gln Glu Arg Gln Ser Ala Leu Glu Glu Ala Gln Gln 225 230 235 240 Asn Pro Arg Glu Gly Ile Val Ile Pro Glu Cys Ala Pro Gly Gly Leu 245 250 255 Tyr Lys Pro Val Gln Cys His Gln Ser Thr Gly Tyr Cys Trp Cys Val 260 265 270 Leu Val Asp Thr Gly Arg Pro Leu Pro Gly Thr Ser Thr Arg Tyr Val 275 280 285 Met Pro Ser Cys Glu Ser Asp Ala Arg Ala Lys Thr Thr Glu Ala Asp 290 295 300 Asp Pro Phe Lys Asp Arg Glu Leu Pro Gly Cys Pro Glu Gly Lys Lys 305 310 315 320 Met Glu Phe Ile Thr Ser Leu Leu Asp Ala Leu Thr Thr Asp Met Val 325 330 335 Gln Ala Ile Asn Ser Ala Ala Pro Thr Gly Gly Gly Arg Phe Ser Glu 340 345 350 Pro Asp Pro Ser His Thr Leu Glu Glu Arg Val Val His Trp Tyr Phe 355 360 365 Ser Gln Leu Asp Ser Asn Ser Ser Asn Asp Ile Asn Lys Arg Glu Met 370 375 380 Lys Pro Phe Lys Arg Tyr Val Lys Lys Lys Ala Lys Pro Lys Glu Cys 385 390 395 400 Ala Arg Arg Phe Thr Asp Tyr Cys Asp Leu Asn Lys Asp Lys Val Ile 405 410 415 Ser Leu Pro Glu Leu Lys Gly Cys Leu Gly Val Ser Lys Glu Val Gly 420 425 430 Arg Leu Val 435 5 1839 DNA Homo sapiens CDS (40)...(1056) 5 gaattcggca cgagcccggc gccatcttca tcgagcgcc atg gcc gca gcc tgc 54 Met Ala Ala Ala Cys 1 5 ggg ccg gga gcg gcc ggg tac tgc ttg ctc ctc ggc ttg cat ttg ttt 102 Gly Pro Gly Ala Ala Gly Tyr Cys Leu Leu Leu Gly Leu His Leu Phe 10 15 20 ctg ctg acc gcg ggc cct gcc ctg ggc tgg aac gac cct gac aga atg 150 Leu Leu Thr Ala Gly Pro Ala Leu Gly Trp Asn Asp Pro Asp Arg Met 25 30 35 ttg ctg cgg gat gta aaa gct ctt acc ctc cac tat gac cgc tat acc 198 Leu Leu Arg Asp Val Lys Ala Leu Thr Leu His Tyr Asp Arg Tyr Thr 40 45 50 acc tcc cgc agg ctg gat ccc atc cca cag ttg aaa tgt gtt gga ggc 246 Thr Ser Arg Arg Leu Asp Pro Ile Pro Gln Leu Lys Cys Val Gly Gly 55 60 65 aca gct ggt tgt gat tct tat acc cca aaa gtc ata cag tgt cag aac 294 Thr Ala Gly Cys Asp Ser Tyr Thr Pro Lys Val Ile Gln Cys Gln Asn 70 75 80 85 aaa ggc tgg gat ggg tat gat gta cag tgg gaa tgt aag acg gac tta 342 Lys Gly Trp Asp Gly Tyr Asp Val Gln Trp Glu Cys Lys Thr Asp Leu 90 95 100 gat att gca tac aaa ttt gga aaa act gtg gtg agc tgt gaa ggc tat 390 Asp Ile Ala Tyr Lys Phe Gly Lys Thr Val Val Ser Cys Glu Gly Tyr 105 110 115 gag tcc tct gaa gac cag tat gta cta aga ggt tct tgt ggc ttg gag 438 Glu Ser Ser Glu Asp Gln Tyr Val Leu Arg Gly Ser Cys Gly Leu Glu 120 125 130 tat aat tta gat tat aca gaa ctt ggc ctg cag aaa ctg aag gag tct 486 Tyr Asn Leu Asp Tyr Thr Glu Leu Gly Leu Gln Lys Leu Lys Glu Ser 135 140 145 gga aag cag cac ggc ttt gcc tct ttc tct gat tat tat tat aag tgg 534 Gly Lys Gln His Gly Phe Ala Ser Phe Ser Asp Tyr Tyr Tyr Lys Trp 150 155 160 165 tcc tcg gcg gat tcc tgt aac atg agt gga ttg att acc atc gtg gta 582 Ser Ser Ala Asp Ser Cys Asn Met Ser Gly Leu Ile Thr Ile Val Val 170 175 180 ctc ctt ggg atc gcc ttt gta gtc tat aag ctg ttc ctg agt gac ggg 630 Leu Leu Gly Ile Ala Phe Val Val Tyr Lys Leu Phe Leu Ser Asp Gly 185 190 195 cag tat tct cct cca ccg tac tct gag tat cct cca ttt tcc cac cgt 678 Gln Tyr Ser Pro Pro Pro Tyr Ser Glu Tyr Pro Pro Phe Ser His Arg 200 205 210 tac cag aga ttc acc aac tca gca gga cct cct ccc cca ggc ttt aag 726 Tyr Gln Arg Phe Thr Asn Ser Ala Gly Pro Pro Pro Pro Gly Phe Lys 215 220 225 tct gag ttc aca gga cca cag aat act ggc cat ggt gca act tct ggt 774 Ser Glu Phe Thr Gly Pro Gln Asn Thr Gly His Gly Ala Thr Ser Gly 230 235 240 245 ttt ggc agt gct ttt aca gga caa caa gga tat gaa aat tca gga cca 822 Phe Gly Ser Ala Phe Thr Gly Gln Gln Gly Tyr Glu Asn Ser Gly Pro 250 255 260 ggg ttc tgg aca ggc ttg gga act ggt gga ata cta gga tat ttg ttt 870 Gly Phe Trp Thr Gly Leu Gly Thr Gly Gly Ile Leu Gly Tyr Leu Phe 265 270 275 ggc agc aat aga gcg gca aca ccc ttc tca gac tcg tgg tac tac ccg 918 Gly Ser Asn Arg Ala Ala Thr Pro Phe Ser Asp Ser Trp Tyr Tyr Pro 280 285 290 tcc tat cct ccc tcc tac cct ggc acg tgg aat agg gct tac tca ccc 966 Ser Tyr Pro Pro Ser Tyr Pro Gly Thr Trp Asn Arg Ala Tyr Ser Pro 295 300 305 ctt cat gga ggc tcg ggc agc tat tcg gta tgt tca aac tca gac acg 1014 Leu His Gly Gly Ser Gly Ser Tyr Ser Val Cys Ser Asn Ser Asp Thr 310 315 320 325 aaa acc aga act gca tca gga tat ggt ggt acc agg aga cga 1056 Lys Thr Arg Thr Ala Ser Gly Tyr Gly Gly Thr Arg Arg Arg 330 335 taaagtagaa agttggagtc aaacactgga tgcagaaatt ttggattttt catcactttc 1116 tctttagaaa aaaagtacta cctgttaaca attgggaaaa ggggatattc aaaagttctg 1176 tggtgttatg tccagtgtag ctttttgtat tctattattt gaggctaaaa gttgatgtgt 1236 gacaaaatac ttatgtgttg tatgtcagtg taacatgcag atgtatattg cagtttttga 1296 aagtgatcat tactgtggaa tgctaaaaat acattaattt ctaaaacctg tgatgcccta 1356 agaagcatta agaatgaagg tgttgtacta atagaaacta agtacagaaa atttcagttt 1416 taggtggttg tagctgatga gttattacct catagagact ataatattct atttggtatt 1476 atattatttg atgtttgctg ttcttcaaac atttaaatca agctttggac taattatgct 1536 aatttgtgag ttctgatcac ttttgagctc tgaagctttg aatcattcag tggtggagat 1596 ggccttctgg taactgaata ttaccttctg taggaaaagg tggaaaataa gcatctagaa 1656 ggttgttgtg aatgactctg tgctggcaaa aatgcttgaa acctctatat ttctttcgtt 1716 cataagaggt aaaggtcaaa tttttcaaca aaagtctttt aataacaaaa gcatgcagtt 1776 ctctgtgaaa tctcaaatat tgttgtaata gtctgtttca atcttaaaaa aaaaaaaaaa 1836 aaa 1839 6 339 PRT Homo sapiens 6 Met Ala Ala Ala Cys Gly Pro Gly Ala Ala Gly Tyr Cys Leu Leu Leu 1 5 10 15 Gly Leu His Leu Phe Leu Leu Thr Ala Gly Pro Ala Leu Gly Trp Asn 20 25 30 Asp Pro Asp Arg Met Leu Leu Arg Asp Val Lys Ala Leu Thr Leu His 35 40 45 Tyr Asp Arg Tyr Thr Thr Ser Arg Arg Leu Asp Pro Ile Pro Gln Leu 50 55 60 Lys Cys Val Gly Gly Thr Ala Gly Cys Asp Ser Tyr Thr Pro Lys Val 65 70 75 80 Ile Gln Cys Gln Asn Lys Gly Trp Asp Gly Tyr Asp Val Gln Trp Glu 85 90 95 Cys Lys Thr Asp Leu Asp Ile Ala Tyr Lys Phe Gly Lys Thr Val Val 100 105 110 Ser Cys Glu Gly Tyr Glu Ser Ser Glu Asp Gln Tyr Val Leu Arg Gly 115 120 125 Ser Cys Gly Leu Glu Tyr Asn Leu Asp Tyr Thr Glu Leu Gly Leu Gln 130 135 140 Lys Leu Lys Glu Ser Gly Lys Gln His Gly Phe Ala Ser Phe Ser Asp 145 150 155 160 Tyr Tyr Tyr Lys Trp Ser Ser Ala Asp Ser Cys Asn Met Ser Gly Leu 165 170 175 Ile Thr Ile Val Val Leu Leu Gly Ile Ala Phe Val Val Tyr Lys Leu 180 185 190 Phe Leu Ser Asp Gly Gln Tyr Ser Pro Pro Pro Tyr Ser Glu Tyr Pro 195 200 205 Pro Phe Ser His Arg Tyr Gln Arg Phe Thr Asn Ser Ala Gly Pro Pro 210 215 220 Pro Pro Gly Phe Lys Ser Glu Phe Thr Gly Pro Gln Asn Thr Gly His 225 230 235 240 Gly Ala Thr Ser Gly Phe Gly Ser Ala Phe Thr Gly Gln Gln Gly Tyr 245 250 255 Glu Asn Ser Gly Pro Gly Phe Trp Thr Gly Leu Gly Thr Gly Gly Ile 260 265 270 Leu Gly Tyr Leu Phe Gly Ser Asn Arg Ala Ala Thr Pro Phe Ser Asp 275 280 285 Ser Trp Tyr Tyr Pro Ser Tyr Pro Pro Ser Tyr Pro Gly Thr Trp Asn 290 295 300 Arg Ala Tyr Ser Pro Leu His Gly Gly Ser Gly Ser Tyr Ser Val Cys 305 310 315 320 Ser Asn Ser Asp Thr Lys Thr Arg Thr Ala Ser Gly Tyr Gly Gly Thr 325 330 335 Arg Arg Arg 7 1831 DNA Homo sapiens CDS (90)...(1286) 7 gaattcggca cgagctggcg gccaccagaa gtttgagcct ctttggtagc aggaggctgg 60 aagaaaggac agaagtagct ctggctgtg atg ggg atc tta ctg ggc ctg cta 113 Met Gly Ile Leu Leu Gly Leu Leu 1 5 ctc ctg ggg cac cta aca gtg gac act tat ggc cgt ccc atc ctg gaa 161 Leu Leu Gly His Leu Thr Val Asp Thr Tyr Gly Arg Pro Ile Leu Glu 10 15 20 gtg cca gag agt gta aca gga cct tgg aaa ggg gat gtg aat ctt ccc 209 Val Pro Glu Ser Val Thr Gly Pro Trp Lys Gly Asp Val Asn Leu Pro 25 30 35 40 tgc acc tat gac ccc ctg caa ggc tac acc caa gtc ttg gtg aag tgg 257 Cys Thr Tyr Asp Pro Leu Gln Gly Tyr Thr Gln Val Leu Val Lys Trp 45 50 55 ctg gta caa cgt ggc tca gac cct gtc acc atc ttt cta cgt gac tct 305 Leu Val Gln Arg Gly Ser Asp Pro Val Thr Ile Phe Leu Arg Asp Ser 60 65 70 tct gga gac cat atc cag cag gca aag tac cag ggc cgc ctg cat gtg 353 Ser Gly Asp His Ile Gln Gln Ala Lys Tyr Gln Gly Arg Leu His Val 75 80 85 agc cac aag gtt cca gga gat gta tcc ctc caa ttg agc acc ctg gag 401 Ser His Lys Val Pro Gly Asp Val Ser Leu Gln Leu Ser Thr Leu Glu 90 95 100 atg gat gac cgg agc cac tac acg tgt gaa gtc acc tgg cag act cct 449 Met Asp Asp Arg Ser His Tyr Thr Cys Glu Val Thr Trp Gln Thr Pro 105 110 115 120 gat ggc aac caa gtc gtg aga gat aag att act gag ctc cgt gtc cag 497 Asp Gly Asn Gln Val Val Arg Asp Lys Ile Thr Glu Leu Arg Val Gln 125 130 135 aaa ctc tct gtc tcc aag ccc aca gtg aca act ggc agc ggt tat ggc 545 Lys Leu Ser Val Ser Lys Pro Thr Val Thr Thr Gly Ser Gly Tyr Gly 140 145 150 ttc acg gtg ccc cag gga atg agg att agc ctt caa tgc cag gct cgg 593 Phe Thr Val Pro Gln Gly Met Arg Ile Ser Leu Gln Cys Gln Ala Arg 155 160 165 ggt tct cct ccc atc agt tat att tgg tat aag caa cag act aat aac 641 Gly Ser Pro Pro Ile Ser Tyr Ile Trp Tyr Lys Gln Gln Thr Asn Asn 170 175 180 cag gaa ccc atc aaa gta gca acc cta agt acc tta ctc ttc aag cct 689 Gln Glu Pro Ile Lys Val Ala Thr Leu Ser Thr Leu Leu Phe Lys Pro 185 190 195 200 gcg gtg ata gcc gac tca ggc tcc tat ttc tgc act gcc aag ggc cag 737 Ala Val Ile Ala Asp Ser Gly Ser Tyr Phe Cys Thr Ala Lys Gly Gln 205 210 215 gtt ggc tct gag cag cac agc gac att gtg aag ttt gtg gtc aaa gac 785 Val Gly Ser Glu Gln His Ser Asp Ile Val Lys Phe Val Val Lys Asp 220 225 230 tcc tca aag cta ctc aag acc aag act gag gca cct aca acc atg aca 833 Ser Ser Lys Leu Leu Lys Thr Lys Thr Glu Ala Pro Thr Thr Met Thr 235 240 245 tac ccc ttg aaa gca aca tct aca gtg aag cag tcc tgg gac tgg acc 881 Tyr Pro Leu Lys Ala Thr Ser Thr Val Lys Gln Ser Trp Asp Trp Thr 250 255 260 act gac atg gat ggc tac ctt gga gag acc agt gct ggg cca gga aag 929 Thr Asp Met Asp Gly Tyr Leu Gly Glu Thr Ser Ala Gly Pro Gly Lys 265 270 275 280 agc ctg cct gtc ttt gcc atc atc ctc atc atc tcc ttg tgc tgt atg 977 Ser Leu Pro Val Phe Ala Ile Ile Leu Ile Ile Ser Leu Cys Cys Met 285 290 295 gtg gtt ttt acc atg gcc tat atc atg ctc tgt cgg aag aca tcc caa 1025 Val Val Phe Thr Met Ala Tyr Ile Met Leu Cys Arg Lys Thr Ser Gln 300 305 310 caa gag cat gtc tac gaa gca gcc agg gca cat gcc aga gag gcc aac 1073 Gln Glu His Val Tyr Glu Ala Ala Arg Ala His Ala Arg Glu Ala Asn 315 320 325 gac tct gga gaa acc atg agg gtg gcc atc ttc gca agt ggc tgc tcc 1121 Asp Ser Gly Glu Thr Met Arg Val Ala Ile Phe Ala Ser Gly Cys Ser 330 335 340 agt gat gag cca act tcc cag aat ctg ggc aac aac tac tct gat gag 1169 Ser Asp Glu Pro Thr Ser Gln Asn Leu Gly Asn Asn Tyr Ser Asp Glu 345 350 355 360 ccc tgc ata gga cag gag tac cag atc atc gcc cag atc aat ggc aac 1217 Pro Cys Ile Gly Gln Glu Tyr Gln Ile Ile Ala Gln Ile Asn Gly Asn 365 370 375 tac gcc cgc ctg ctg gac aca gtt cct ctg gat tat gag ttt ctg gcc 1265 Tyr Ala Arg Leu Leu Asp Thr Val Pro Leu Asp Tyr Glu Phe Leu Ala 380 385 390 act gag ggc aaa agt gtc tgt taaaaatgcc ccattaggcc aggatctgct 1316 Thr Glu Gly Lys Ser Val Cys 395 gacataattg cctagtcagt ccttgccttc tgcatggcct tcttccctgc tacctctctt 1376 cctggatagc ccaaagtgtc cgcctaccaa cactggagcc gctgggagtc actggctttg 1436 ccctggaatt tgccagatgc atctcaagta agccagctgc tggatttggc tctgggccct 1496 tctagtatct ctgccggggg cttctggtac tcctctctaa ataccagagg gaagatgccc 1556 atagcactag gacttggtca tcatgcctac agacactatt caactttggc atcttgccac 1616 cagaagaccc gagggaggct cagctctgcc agctcagagg accagctata ttcaggatca 1676 tttctctttc ttcagggcca gacagctttt aattgaaatt gttatttcac aggccagggt 1736 tcagttctgc tcctccacta taagtctaat gttctgactc tctcctggtg ctcaataaat 1796 atctaatcat aacagcaaaa aaaaaaaaaa aaaaa 1831 8 399 PRT Homo sapiens 8 Met Gly Ile Leu Leu Gly Leu Leu Leu Leu Gly His Leu Thr Val Asp 1 5 10 15 Thr Tyr Gly Arg Pro Ile Leu Glu Val Pro Glu Ser Val Thr Gly Pro 20 25 30 Trp Lys Gly Asp Val Asn Leu Pro Cys Thr Tyr Asp Pro Leu Gln Gly 35 40 45 Tyr Thr Gln Val Leu Val Lys Trp Leu Val Gln Arg Gly Ser Asp Pro 50 55 60 Val Thr Ile Phe Leu Arg Asp Ser Ser Gly Asp His Ile Gln Gln Ala 65 70 75 80 Lys Tyr Gln Gly Arg Leu His Val Ser His Lys Val Pro Gly Asp Val 85 90 95 Ser Leu Gln Leu Ser Thr Leu Glu Met Asp Asp Arg Ser His Tyr Thr 100 105 110 Cys Glu Val Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Val Arg Asp 115 120 125 Lys Ile Thr Glu Leu Arg Val Gln Lys Leu Ser Val Ser Lys Pro Thr 130 135 140 Val Thr Thr Gly Ser Gly Tyr Gly Phe Thr Val Pro Gln Gly Met Arg 145 150 155 160 Ile Ser Leu Gln Cys Gln Ala Arg Gly Ser Pro Pro Ile Ser Tyr Ile 165 170 175 Trp Tyr Lys Gln Gln Thr Asn Asn Gln Glu Pro Ile Lys Val Ala Thr 180 185 190 Leu Ser Thr Leu Leu Phe Lys Pro Ala Val Ile Ala Asp Ser Gly Ser 195 200 205 Tyr Phe Cys Thr Ala Lys Gly Gln Val Gly Ser Glu Gln His Ser Asp 210 215 220 Ile Val Lys Phe Val Val Lys Asp Ser Ser Lys Leu Leu Lys Thr Lys 225 230 235 240 Thr Glu Ala Pro Thr Thr Met Thr Tyr Pro Leu Lys Ala Thr Ser Thr 245 250 255 Val Lys Gln Ser Trp Asp Trp Thr Thr Asp Met Asp Gly Tyr Leu Gly 260 265 270 Glu Thr Ser Ala Gly Pro Gly Lys Ser Leu Pro Val Phe Ala Ile Ile 275 280 285 Leu Ile Ile Ser Leu Cys Cys Met Val Val Phe Thr Met Ala Tyr Ile 290 295 300 Met Leu Cys Arg Lys Thr Ser Gln Gln Glu His Val Tyr Glu Ala Ala 305 310 315 320 Arg Ala His Ala Arg Glu Ala Asn Asp Ser Gly Glu Thr Met Arg Val 325 330 335 Ala Ile Phe Ala Ser Gly Cys Ser Ser Asp Glu Pro Thr Ser Gln Asn 340 345 350 Leu Gly Asn Asn Tyr Ser Asp Glu Pro Cys Ile Gly Gln Glu Tyr Gln 355 360 365 Ile Ile Ala Gln Ile Asn Gly Asn Tyr Ala Arg Leu Leu Asp Thr Val 370 375 380 Pro Leu Asp Tyr Glu Phe Leu Ala Thr Glu Gly Lys Ser Val Cys 385 390 395 9 4222 DNA Homo sapiens CDS (238)...(2364) 9 ggatccaaag aattcggcac gagagactcc ctaacctgtg tctggacaag tctgatgtcc 60 tgtgtggccc aagaagaact gaccccgtgt ctggagctcc caccgttatt gcatccctgc 120 tgtggctcac ctgctgctgt ctccaggagc ccctgagaag atttgcctcc tctcccctgc 180 taagctccag gtcctgagat tgaattaggg gctggagctc actgcactcc agcagtc atg 240 Met 1 gga ccc agg ata ggg cca gcg ggt gag gta ccc cag gta cca gac aag 288 Gly Pro Arg Ile Gly Pro Ala Gly Glu Val Pro Gln Val Pro Asp Lys 5 10 15 gaa acc aaa gcc aca atg ggc aca gaa aac aca cct gga ggc aaa gcc 336 Glu Thr Lys Ala Thr Met Gly Thr Glu Asn Thr Pro Gly Gly Lys Ala 20 25 30 agc cca gac cct cag gac gtg cgg cca agt gtg ttc cat aac atc aag 384 Ser Pro Asp Pro Gln Asp Val Arg Pro Ser Val Phe His Asn Ile Lys 35 40 45 ctg ttc gtt ctg tgc cac agc ctg ctg cag ctg gcg cag ctc atg atc 432 Leu Phe Val Leu Cys His Ser Leu Leu Gln Leu Ala Gln Leu Met Ile 50 55 60 65 tcc ggc tac cta aag agc tcc atc tcc aca gtg gag aag cgc ttc ggc 480 Ser Gly Tyr Leu Lys Ser Ser Ile Ser Thr Val Glu Lys Arg Phe Gly 70 75 80 ctc tcc agc cag acg tcg ggg ctg ctg gcc tcc ttc aac gag gtg ggg 528 Leu Ser Ser Gln Thr Ser Gly Leu Leu Ala Ser Phe Asn Glu Val Gly 85 90 95 aac aca gcc ttg att gtg ttt gtg agc tat ttt ggc agc cgg gtg cac 576 Asn Thr Ala Leu Ile Val Phe Val Ser Tyr Phe Gly Ser Arg Val His 100 105 110 cga ccc cga atg att ggc tat ggg gct atc ctt gtg gcc ctg gcg ggc 624 Arg Pro Arg Met Ile Gly Tyr Gly Ala Ile Leu Val Ala Leu Ala Gly 115 120 125 ctg ctc atg act ctc ccg cac ttc atc tcg gag cca tac cgc tac gac 672 Leu Leu Met Thr Leu Pro His Phe Ile Ser Glu Pro Tyr Arg Tyr Asp 130 135 140 145 aac acc agc cct gag gat atg cca cag gac ttc aag gct tcc ctg tgc 720 Asn Thr Ser Pro Glu Asp Met Pro Gln Asp Phe Lys Ala Ser Leu Cys 150 155 160 ctg ccc aca acc tcg gcc cca gcc tcg gcc ccc tcc aat ggc aac tgc 768 Leu Pro Thr Thr Ser Ala Pro Ala Ser Ala Pro Ser Asn Gly Asn Cys 165 170 175 tca agc tac aca gaa acc cag cat ctg agt gtg gtg ggg atc atg ttc 816 Ser Ser Tyr Thr Glu Thr Gln His Leu Ser Val Val Gly Ile Met Phe 180 185 190 gtg gca cag acc ctg ctg ggc gtg ggc ggg gtg ccc att cag ccc ttt 864 Val Ala Gln Thr Leu Leu Gly Val Gly Gly Val Pro Ile Gln Pro Phe 195 200 205 ggc atc tcc tac atc gat gac ttt gcc cac aac agc aac tcg ccc ctc 912 Gly Ile Ser Tyr Ile Asp Asp Phe Ala His Asn Ser Asn Ser Pro Leu 210 215 220 225 tac ctc ggg atc ctg ttt gca gtg acc atg atg ggg cca ggc ctg gcc 960 Tyr Leu Gly Ile Leu Phe Ala Val Thr Met Met Gly Pro Gly Leu Ala 230 235 240 ttt ggg ctg ggc agc ctc atg ctg cgc ctt tat gtg gac att aac cag 1008 Phe Gly Leu Gly Ser Leu Met Leu Arg Leu Tyr Val Asp Ile Asn Gln 245 250 255 atg cca gaa ggt ggt atc agc ctg acc ata aag gac ccc cga tgg gtg 1056 Met Pro Glu Gly Gly Ile Ser Leu Thr Ile Lys Asp Pro Arg Trp Val 260 265 270 ggt gcc tgg tgg ctg ggt ttc ctc atc gct gcc ggt gca gtg gcc ctg 1104 Gly Ala Trp Trp Leu Gly Phe Leu Ile Ala Ala Gly Ala Val Ala Leu 275 280 285 gct gcc atc ccc tac ttc ttc ttc ccc aag gaa atg ccc aag gaa aaa 1152 Ala Ala Ile Pro Tyr Phe Phe Phe Pro Lys Glu Met Pro Lys Glu Lys 290 295 300 305 cgt gag ctt cag ttt cgg cga aag gtc tta gca gtc aca gac tca cct 1200 Arg Glu Leu Gln Phe Arg Arg Lys Val Leu Ala Val Thr Asp Ser Pro 310 315 320 gcc agg aag ggc aag gac tct ccc tct aag cag agc cct ggg gag tcc 1248 Ala Arg Lys Gly Lys Asp Ser Pro Ser Lys Gln Ser Pro Gly Glu Ser 325 330 335 acg aag aag cag gat ggc cta gtc cag att gca cca aac ctg act gtg 1296 Thr Lys Lys Gln Asp Gly Leu Val Gln Ile Ala Pro Asn Leu Thr Val 340 345 350 atc cag ttc att aaa gtc ttc ccc agg gtg ctg ctg cag acc cta cgc 1344 Ile Gln Phe Ile Lys Val Phe Pro Arg Val Leu Leu Gln Thr Leu Arg 355 360 365 cac ccc atc ttc ctg ctg gtg gtc ctg tcc cag gta tgc ttg tca tcc 1392 His Pro Ile Phe Leu Leu Val Val Leu Ser Gln Val Cys Leu Ser Ser 370 375 380 385 atg gct gcg ggc atg gcc acc ttc ctg ccc aag ttc ctg gag cgc cag 1440 Met Ala Ala Gly Met Ala Thr Phe Leu Pro Lys Phe Leu Glu Arg Gln 390 395 400 ttt tcc atc aca gcc tcc tac gcc aac ctg ctc atc ggc tgc ctc tcc 1488 Phe Ser Ile Thr Ala Ser Tyr Ala Asn Leu Leu Ile Gly Cys Leu Ser 405 410 415 ttc cct tcg gtc atc gtg ggc atc gtg gtg ggt ggc gtc ctg gtc aag 1536 Phe Pro Ser Val Ile Val Gly Ile Val Val Gly Gly Val Leu Val Lys 420 425 430 cgg ctc cac ctg ggc cct gtg gga tgc ggt gcc ctt tgc ctg ctg ggg 1584 Arg Leu His Leu Gly Pro Val Gly Cys Gly Ala Leu Cys Leu Leu Gly 435 440 445 atg ctg ctg tgc ctc ttc ttc agc ctg ccg ctc ttc ttt atc ggc tgc 1632 Met Leu Leu Cys Leu Phe Phe Ser Leu Pro Leu Phe Phe Ile Gly Cys 450 455 460 465 tcc agc cac cag att gcg ggc atc aca cac cag acc agt gcc cac cct 1680 Ser Ser His Gln Ile Ala Gly Ile Thr His Gln Thr Ser Ala His Pro 470 475 480 ggg ctg gag ctg tct cca agc tgc atg gag gcc tgc tcc tgc cca ttg 1728 Gly Leu Glu Leu Ser Pro Ser Cys Met Glu Ala Cys Ser Cys Pro Leu 485 490 495 gac ggc ttt aac cct gtc tgc gac ccc agc act cgt gtg gaa tac atc 1776 Asp Gly Phe Asn Pro Val Cys Asp Pro Ser Thr Arg Val Glu Tyr Ile 500 505 510 aca ccc tgc cac gca ggc tgc tca agc tgg gtg gtc cag gat gct ctg 1824 Thr Pro Cys His Ala Gly Cys Ser Ser Trp Val Val Gln Asp Ala Leu 515 520 525 gac aac agc cag gtt ttc tac acc aac tgc agc tgc gtg gtg gag ggc 1872 Asp Asn Ser Gln Val Phe Tyr Thr Asn Cys Ser Cys Val Val Glu Gly 530 535 540 545 aac ccc gtg ctg gca gga tcc tgc gac tca acg tgc agc cat ctg gtg 1920 Asn Pro Val Leu Ala Gly Ser Cys Asp Ser Thr Cys Ser His Leu Val 550 555 560 gtg ccc ttc ctg ctc ctg gtc agc ctg ggc tcg gcc ctg gcc tgt ctc 1968 Val Pro Phe Leu Leu Leu Val Ser Leu Gly Ser Ala Leu Ala Cys Leu 565 570 575 acc cac aca ccc tcc ttc atg ctc atc cta aga gga gtg aag aaa gaa 2016 Thr His Thr Pro Ser Phe Met Leu Ile Leu Arg Gly Val Lys Lys Glu 580 585 590 gac aag act ttg gct gtg ggc atc cag ttc atg ttc ctg agg att ttg 2064 Asp Lys Thr Leu Ala Val Gly Ile Gln Phe Met Phe Leu Arg Ile Leu 595 600 605 gcc tgg atg ccc agc ccc gtg atc cac ggc agc gcc atc gac acc acc 2112 Ala Trp Met Pro Ser Pro Val Ile His Gly Ser Ala Ile Asp Thr Thr 610 615 620 625 tgt gtg cac tgg gcc ctg agc tgt ggg cgt cga gct gtc tgt cgc tac 2160 Cys Val His Trp Ala Leu Ser Cys Gly Arg Arg Ala Val Cys Arg Tyr 630 635 640 tac aat aat gac ctg ctc cga aac cgg ttc atc ggc ctc cag ttc ttc 2208 Tyr Asn Asn Asp Leu Leu Arg Asn Arg Phe Ile Gly Leu Gln Phe Phe 645 650 655 ttc aaa aca ggt tct gtg atc tgc ttc gcc tta gtt ttg gct gtc ctg 2256 Phe Lys Thr Gly Ser Val Ile Cys Phe Ala Leu Val Leu Ala Val Leu 660 665 670 agg cag cag gac aaa gag gca agg acc aaa gag agc aga tcc agc cct 2304 Arg Gln Gln Asp Lys Glu Ala Arg Thr Lys Glu Ser Arg Ser Ser Pro 675 680 685 gcc gta gag cag caa ttg cta gtg tcg ggg cca ggg aag aag cca gag 2352 Ala Val Glu Gln Gln Leu Leu Val Ser Gly Pro Gly Lys Lys Pro Glu 690 695 700 705 gat tcc cga gtg tgagctgtct tggggcccca cctggccaag agtagcagcc 2404 Asp Ser Arg Val acagcagtac ctcctctgag tcctttgccc aagattgggt gtcaagagcc ctgtgttcca 2464 ttctggctcc tccactaaat tgctgtgtga cttcaggcaa gacattgatc ctctctcagc 2524 ctttgcttgc tagtctgaac caaagagttg tttgggcatt tgctgtgttg gccatttctg 2584 gagcaagagg gtcttcttcc tccttccccc agccagccag ctgtcctggg gccaggcttt 2644 cctgggtgga aagaagtata cctttccctg gggccctagg atagcaaagt gagccatagt 2704 gggccaggct gccctccatg ctgggcccca gcccaggtct gcactcgcct ggatcacctt 2764 ctttgagcct tagccatctc ctgtcaggta ggaatgaact tgccagcctt caggctcgtt 2824 cagctatgac catctgtgcg gtcagggtac actcagctct cctccccaac tccagcagcc 2884 tttaagaagt gtccctttgg cgccccctgg aggcagagca ctgagctgga ccctgggtag 2944 actcccacag ggaggacgga gctggcctca ggagtgggac acccagactt ggcagggcct 3004 tcaagaggcc tgtgtggggg ccccaggaat ccttagctga agcggggaga ctcactctcc 3064 atctcaggaa attctagccc ttgccctcag ggagccacgg ttgagggtga ggcccaacac 3124 ctgccttagg gccctgggtg ggcaagtctg ggccctgggg tagggaggga gactcaggcc 3184 cacacttggg tattttctaa tttcagacaa acacacactc agcgcgcact cactgattcc 3244 tacacattgc caagatttca cacatgtgac caggggccac caaagtccct gtgacctttg 3304 tgactaggat cctaatttct ctattttctc ctgggtgcct gggtctgtgt cacctggggc 3364 agtgtggata atgtttagtt ctgtgacact gttttttggg ggtggcacct ggttctccga 3424 tgcctgggct ggtgtcaggc ccaggactgt agtgctggga gcagtaaagc tcagctctgt 3484 gtaatgagtg atgctatggc ttgctcgtgt cttatgatcc aatccttttc tacatcagcc 3544 cttgttttgt tttatggcta gtcttatctg gcctggttat ttccttgcgg ggaggagagg 3604 gtttgctaat ctgctcccag cccaacctat taccacccca cctcgctggg acctactgct 3664 cgggaggcag cagacaggga gccaccagca gtggcttcct ggccctgtgc tgggggtggg 3724 gggaagctgg gggcacatgt ggcccttgcc ttctgagcag ctcccagtgc cagggctttg 3784 agactttccc acatgataaa agaaaaggga ggtacagaag ttccaattcc ctttttattt 3844 tgctggttgg tatctgtaaa tgtttaataa atatctgagc atgtatctat caacgccaag 3904 aatttcaaag tctccttcaa caatatgagg cttttaggat gtttatattc cttcatccct 3964 cttgtttccc aggttttgca gggaaaaaaa gtctggaatt atagatacag cttattatta 4024 aatttgttct tgcataatgt ctcttctatt acaaaaattc tttcttcata aactgcatta 4084 gaggtttgca acaaccacat catttccatt aacttagatt taggttttac tggattcatt 4144 gctcaccatt attgcttgta tattacatct tttccaatct ttaaaaaaaa aaaaaaaaaa 4204 ctcgagagta cttctaga 4222 10 709 PRT Homo sapiens 10 Met Gly Pro Arg Ile Gly Pro Ala Gly Glu Val Pro Gln Val Pro Asp 1 5 10 15 Lys Glu Thr Lys Ala Thr Met Gly Thr Glu Asn Thr Pro Gly Gly Lys 20 25 30 Ala Ser Pro Asp Pro Gln Asp Val Arg Pro Ser Val Phe His Asn Ile 35 40 45 Lys Leu Phe Val Leu Cys His Ser Leu Leu Gln Leu Ala Gln Leu Met 50 55 60 Ile Ser Gly Tyr Leu Lys Ser Ser Ile Ser Thr Val Glu Lys Arg Phe 65 70 75 80 Gly Leu Ser Ser Gln Thr Ser Gly Leu Leu Ala Ser Phe Asn Glu Val 85 90 95 Gly Asn Thr Ala Leu Ile Val Phe Val Ser Tyr Phe Gly Ser Arg Val 100 105 110 His Arg Pro Arg Met Ile Gly Tyr Gly Ala Ile Leu Val Ala Leu Ala 115 120 125 Gly Leu Leu Met Thr Leu Pro His Phe Ile Ser Glu Pro Tyr Arg Tyr 130 135 140 Asp Asn Thr Ser Pro Glu Asp Met Pro Gln Asp Phe Lys Ala Ser Leu 145 150 155 160 Cys Leu Pro Thr Thr Ser Ala Pro Ala Ser Ala Pro Ser Asn Gly Asn 165 170 175 Cys Ser Ser Tyr Thr Glu Thr Gln His Leu Ser Val Val Gly Ile Met 180 185 190 Phe Val Ala Gln Thr Leu Leu Gly Val Gly Gly Val Pro Ile Gln Pro 195 200 205 Phe Gly Ile Ser Tyr Ile Asp Asp Phe Ala His Asn Ser Asn Ser Pro 210 215 220 Leu Tyr Leu Gly Ile Leu Phe Ala Val Thr Met Met Gly Pro Gly Leu 225 230 235 240 Ala Phe Gly Leu Gly Ser Leu Met Leu Arg Leu Tyr Val Asp Ile Asn 245 250 255 Gln Met Pro Glu Gly Gly Ile Ser Leu Thr Ile Lys Asp Pro Arg Trp 260 265 270 Val Gly Ala Trp Trp Leu Gly Phe Leu Ile Ala Ala Gly Ala Val Ala 275 280 285 Leu Ala Ala Ile Pro Tyr Phe Phe Phe Pro Lys Glu Met Pro Lys Glu 290 295 300 Lys Arg Glu Leu Gln Phe Arg Arg Lys Val Leu Ala Val Thr Asp Ser 305 310 315 320 Pro Ala Arg Lys Gly Lys Asp Ser Pro Ser Lys Gln Ser Pro Gly Glu 325 330 335 Ser Thr Lys Lys Gln Asp Gly Leu Val Gln Ile Ala Pro Asn Leu Thr 340 345 350 Val Ile Gln Phe Ile Lys Val Phe Pro Arg Val Leu Leu Gln Thr Leu 355 360 365 Arg His Pro Ile Phe Leu Leu Val Val Leu Ser Gln Val Cys Leu Ser 370 375 380 Ser Met Ala Ala Gly Met Ala Thr Phe Leu Pro Lys Phe Leu Glu Arg 385 390 395 400 Gln Phe Ser Ile Thr Ala Ser Tyr Ala Asn Leu Leu Ile Gly Cys Leu 405 410 415 Ser Phe Pro Ser Val Ile Val Gly Ile Val Val Gly Gly Val Leu Val 420 425 430 Lys Arg Leu His Leu Gly Pro Val Gly Cys Gly Ala Leu Cys Leu Leu 435 440 445 Gly Met Leu Leu Cys Leu Phe Phe Ser Leu Pro Leu Phe Phe Ile Gly 450 455 460 Cys Ser Ser His Gln Ile Ala Gly Ile Thr His Gln Thr Ser Ala His 465 470 475 480 Pro Gly Leu Glu Leu Ser Pro Ser Cys Met Glu Ala Cys Ser Cys Pro 485 490 495 Leu Asp Gly Phe Asn Pro Val Cys Asp Pro Ser Thr Arg Val Glu Tyr 500 505 510 Ile Thr Pro Cys His Ala Gly Cys Ser Ser Trp Val Val Gln Asp Ala 515 520 525 Leu Asp Asn Ser Gln Val Phe Tyr Thr Asn Cys Ser Cys Val Val Glu 530 535 540 Gly Asn Pro Val Leu Ala Gly Ser Cys Asp Ser Thr Cys Ser His Leu 545 550 555 560 Val Val Pro Phe Leu Leu Leu Val Ser Leu Gly Ser Ala Leu Ala Cys 565 570 575 Leu Thr His Thr Pro Ser Phe Met Leu Ile Leu Arg Gly Val Lys Lys 580 585 590 Glu Asp Lys Thr Leu Ala Val Gly Ile Gln Phe Met Phe Leu Arg Ile 595 600 605 Leu Ala Trp Met Pro Ser Pro Val Ile His Gly Ser Ala Ile Asp Thr 610 615 620 Thr Cys Val His Trp Ala Leu Ser Cys Gly Arg Arg Ala Val Cys Arg 625 630 635 640 Tyr Tyr Asn Asn Asp Leu Leu Arg Asn Arg Phe Ile Gly Leu Gln Phe 645 650 655 Phe Phe Lys Thr Gly Ser Val Ile Cys Phe Ala Leu Val Leu Ala Val 660 665 670 Leu Arg Gln Gln Asp Lys Glu Ala Arg Thr Lys Glu Ser Arg Ser Ser 675 680 685 Pro Ala Val Glu Gln Gln Leu Leu Val Ser Gly Pro Gly Lys Lys Pro 690 695 700 Glu Asp Ser Arg Val 705 11 960 DNA Homo sapiens CDS (78)...(797) 11 gaattcggca cgagggccgg cctccgcccg gccccgaggg caggctctcc ccggaggctc 60 agccccctct gctcccc atg ggc aac tgc cag gca ggg cac aac ctg cac 110 Met Gly Asn Cys Gln Ala Gly His Asn Leu His 1 5 10 ctg tgt ctg gcc cac cac cca cct ctg gtc tgt gcc act ttg atc ctg 158 Leu Cys Leu Ala His His Pro Pro Leu Val Cys Ala Thr Leu Ile Leu 15 20 25 ctg ctc ctt ggc ctc tct ggc ctg ggc ctt ggc agc ttc ctc ctc acc 206 Leu Leu Leu Gly Leu Ser Gly Leu Gly Leu Gly Ser Phe Leu Leu Thr 30 35 40 cac agg act ggc ctg cgc agc cct gac atc ccc cag gac tgg gtc tct 254 His Arg Thr Gly Leu Arg Ser Pro Asp Ile Pro Gln Asp Trp Val Ser 45 50 55 ttt ttg aga tct ttt ggc cag ctg acc ctg tgt ccc agg aat ggg aca 302 Phe Leu Arg Ser Phe Gly Gln Leu Thr Leu Cys Pro Arg Asn Gly Thr 60 65 70 75 gtc aca ggg aag tgg cga ggg tct cac gtc gtg ggc ttg ctg acc acc 350 Val Thr Gly Lys Trp Arg Gly Ser His Val Val Gly Leu Leu Thr Thr 80 85 90 ttg aac ttc gga gac ggt cca gac agg aac aag acc cgg aca ttc cag 398 Leu Asn Phe Gly Asp Gly Pro Asp Arg Asn Lys Thr Arg Thr Phe Gln 95 100 105 gcc aca gtc ctg gga agt cag atg gga ttg aaa gga tct tct gca gga 446 Ala Thr Val Leu Gly Ser Gln Met Gly Leu Lys Gly Ser Ser Ala Gly 110 115 120 caa ctg gtc ctt atc aca gcc agg gtg acc aca gaa agg act gca gga 494 Gln Leu Val Leu Ile Thr Ala Arg Val Thr Thr Glu Arg Thr Ala Gly 125 130 135 acc tgc cta tat ttt agt gct gtt cca gga atc cta ccc tcc agc cag 542 Thr Cys Leu Tyr Phe Ser Ala Val Pro Gly Ile Leu Pro Ser Ser Gln 140 145 150 155 cca ccc ata tcc tgc tca gag gag ggg gct gga aat gcc acc ctg agc 590 Pro Pro Ile Ser Cys Ser Glu Glu Gly Ala Gly Asn Ala Thr Leu Ser 160 165 170 cct aga atg ggt gag gaa tgt gtt agt gtc tgg agc cat gaa ggc ctt 638 Pro Arg Met Gly Glu Glu Cys Val Ser Val Trp Ser His Glu Gly Leu 175 180 185 gtg ctg acc aag ctg ctc acc tcg gag gag ctg gct ctg tgt ggc tcc 686 Val Leu Thr Lys Leu Leu Thr Ser Glu Glu Leu Ala Leu Cys Gly Ser 190 195 200 agg ctg ctg gtc ttg ggc tcc ttc ctg ctt ctc ttc tgt ggc ctt ctc 734 Arg Leu Leu Val Leu Gly Ser Phe Leu Leu Leu Phe Cys Gly Leu Leu 205 210 215 tgc tgt gtc act gct atg tgc ttc cac ccg cgc cgg gag tcc cac tgg 782 Cys Cys Val Thr Ala Met Cys Phe His Pro Arg Arg Glu Ser His Trp 220 225 230 235 tct aga acc cgg ctc tgagggcact ggcctagttc ccgacttgtt tctcaggtgt 837 Ser Arg Thr Arg Leu 240 gaatcaactt cttgggcctt ggctctgagt tggaaaaggt tttagaaaaa gtgaagagct 897 ggaatgtggg ggaaaataaa aagctttttt gcccaaaaaa aaaaaaaaaa aaaaaaaaaa 957 aaa 960 12 240 PRT Homo sapiens 12 Met Gly Asn Cys Gln Ala Gly His Asn Leu His Leu Cys Leu Ala His 1 5 10 15 His Pro Pro Leu Val Cys Ala Thr Leu Ile Leu Leu Leu Leu Gly Leu 20 25 30 Ser Gly Leu Gly Leu Gly Ser Phe Leu Leu Thr His Arg Thr Gly Leu 35 40 45 Arg Ser Pro Asp Ile Pro Gln Asp Trp Val Ser Phe Leu Arg Ser Phe 50 55 60 Gly Gln Leu Thr Leu Cys Pro Arg Asn Gly Thr Val Thr Gly Lys Trp 65 70 75 80 Arg Gly Ser His Val Val Gly Leu Leu Thr Thr Leu Asn Phe Gly Asp 85 90 95 Gly Pro Asp Arg Asn Lys Thr Arg Thr Phe Gln Ala Thr Val Leu Gly 100 105 110 Ser Gln Met Gly Leu Lys Gly Ser Ser Ala Gly Gln Leu Val Leu Ile 115 120 125 Thr Ala Arg Val Thr Thr Glu Arg Thr Ala Gly Thr Cys Leu Tyr Phe 130 135 140 Ser Ala Val Pro Gly Ile Leu Pro Ser Ser Gln Pro Pro Ile Ser Cys 145 150 155 160 Ser Glu Glu Gly Ala Gly Asn Ala Thr Leu Ser Pro Arg Met Gly Glu 165 170 175 Glu Cys Val Ser Val Trp Ser His Glu Gly Leu Val Leu Thr Lys Leu 180 185 190 Leu Thr Ser Glu Glu Leu Ala Leu Cys Gly Ser Arg Leu Leu Val Leu 195 200 205 Gly Ser Phe Leu Leu Leu Phe Cys Gly Leu Leu Cys Cys Val Thr Ala 210 215 220 Met Cys Phe His Pro Arg Arg Glu Ser His Trp Ser Arg Thr Arg Leu 225 230 235 240 13 2832 DNA Homo sapiens CDS (317)...(2155) 13 ggatccaaag aattcggcac gaggctggct cagcccagag tccctgtctc ccgcccgccg 60 gcccgagccg ccgcccctcc cccgcctccc gtgcgcccgg gacaatcctc gccttgtctg 120 tggcgccggc atctggagct ttctgtagcc tccggatacg cctttttttc agggcgtagc 180 cccagccaag ctgctccccg cggcggccgc acagcagccc gagcgccccc tttccggagc 240 tcccctccgg agctgggatc caggcgcgta gcggagatcc caggatcctg ggtgctgtct 300 gggcccgctc cccacc atg acc ttc ttg ggg cct gga ccc cgg ttc ctg ctg 352 Met Thr Phe Leu Gly Pro Gly Pro Arg Phe Leu Leu 1 5 10 ctg ctg ccg ctg ctg ctg ccc cct gcg gcc tca gcc tcc gac cgg ccc 400 Leu Leu Pro Leu Leu Leu Pro Pro Ala Ala Ser Ala Ser Asp Arg Pro 15 20 25 cgg ggc cga gac ccg gtc aac cca gag aag ctg ctg gtg atc act gtg 448 Arg Gly Arg Asp Pro Val Asn Pro Glu Lys Leu Leu Val Ile Thr Val 30 35 40 gcc aca gct gaa acc gag ggg tac ctg cgt ttc ctg cgc tct gcg gag 496 Ala Thr Ala Glu Thr Glu Gly Tyr Leu Arg Phe Leu Arg Ser Ala Glu 45 50 55 60 ttc ttc aac tac act gtg cgg acc ctg ggc ctg gga gag gag tgg cga 544 Phe Phe Asn Tyr Thr Val Arg Thr Leu Gly Leu Gly Glu Glu Trp Arg 65 70 75 ggg ggt gat gtg gct cga aca gtt ggt gga gga cag aag gtc cgg tgg 592 Gly Gly Asp Val Ala Arg Thr Val Gly Gly Gly Gln Lys Val Arg Trp 80 85 90 tta aag aag gaa atg gag aaa tac gct gac cgg gag gat atg atc atc 640 Leu Lys Lys Glu Met Glu Lys Tyr Ala Asp Arg Glu Asp Met Ile Ile 95 100 105 atg ttt gtg gat agc tac gac gtg att ctg gcc ggc agc ccc aca gag 688 Met Phe Val Asp Ser Tyr Asp Val Ile Leu Ala Gly Ser Pro Thr Glu 110 115 120 ctg ctg aag aag ttc gtc cag agt ggc agc cgc ctg ctc ttc tct gca 736 Leu Leu Lys Lys Phe Val Gln Ser Gly Ser Arg Leu Leu Phe Ser Ala 125 130 135 140 gag agc ttc tgc tgg ccc gag tgg ggg ctg gcg gag cag tac cct gag 784 Glu Ser Phe Cys Trp Pro Glu Trp Gly Leu Ala Glu Gln Tyr Pro Glu 145 150 155 gtg ggc acg ggg aag cgc ttc ctc aat tct ggt gga ttc atc ggt ttt 832 Val Gly Thr Gly Lys Arg Phe Leu Asn Ser Gly Gly Phe Ile Gly Phe 160 165 170 gcc acc acc atc cac caa atc gtg cgc cag tgg aag tac aag gat gat 880 Ala Thr Thr Ile His Gln Ile Val Arg Gln Trp Lys Tyr Lys Asp Asp 175 180 185 gac gac gac cag ctg ttc tac aca cgg ctc tac ctg gac cca gga ctg 928 Asp Asp Asp Gln Leu Phe Tyr Thr Arg Leu Tyr Leu Asp Pro Gly Leu 190 195 200 agg gag aaa ctc agc ctt aat ctg gat cat aag tct cgg atc ttt cag 976 Arg Glu Lys Leu Ser Leu Asn Leu Asp His Lys Ser Arg Ile Phe Gln 205 210 215 220 aac ctc aac ggg gct tta gat gaa gtg gtt tta aag ttt gat cgg aac 1024 Asn Leu Asn Gly Ala Leu Asp Glu Val Val Leu Lys Phe Asp Arg Asn 225 230 235 cgt gtg cgt atc cgg aac gtg gcc tac gac acg ctc ccc att gtg gtc 1072 Arg Val Arg Ile Arg Asn Val Ala Tyr Asp Thr Leu Pro Ile Val Val 240 245 250 cat gga aac ggt ccc act aag ctg cag ctc aac tac ctg gga aac tac 1120 His Gly Asn Gly Pro Thr Lys Leu Gln Leu Asn Tyr Leu Gly Asn Tyr 255 260 265 gtc ccc aat ggc tgg act cct gag gga ggc tgt ggc ttc tgc aac cag 1168 Val Pro Asn Gly Trp Thr Pro Glu Gly Gly Cys Gly Phe Cys Asn Gln 270 275 280 gac cgg agg aca ctc ccg ggg ggg cag cct ccc ccc cgg gtg ttt ctg 1216 Asp Arg Arg Thr Leu Pro Gly Gly Gln Pro Pro Pro Arg Val Phe Leu 285 290 295 300 gcc gtg ttt gtg gaa cag cct act ccg ttt ctg ccc cgc ttc ctg cag 1264 Ala Val Phe Val Glu Gln Pro Thr Pro Phe Leu Pro Arg Phe Leu Gln 305 310 315 cgg ctg cta ctc ctg gac tat ccc ccc gac agg gtc acc ctt ttc ctg 1312 Arg Leu Leu Leu Leu Asp Tyr Pro Pro Asp Arg Val Thr Leu Phe Leu 320 325 330 cac aac aac gag gtc ttc cat gaa ccc cac atc gct gac tcc tgg ccg 1360 His Asn Asn Glu Val Phe His Glu Pro His Ile Ala Asp Ser Trp Pro 335 340 345 cag ctc cag gac cac ttc tca gct gtg aag ctc gtg ggg ccg gag gag 1408 Gln Leu Gln Asp His Phe Ser Ala Val Lys Leu Val Gly Pro Glu Glu 350 355 360 gct ctg agc cca ggc gag gcc agg gac atg gcc atg gac ctg tgt cgg 1456 Ala Leu Ser Pro Gly Glu Ala Arg Asp Met Ala Met Asp Leu Cys Arg 365 370 375 380 cag gac ccc gag tgt gag ttc tac ttc agc ctg gac gcc gac gct gtc 1504 Gln Asp Pro Glu Cys Glu Phe Tyr Phe Ser Leu Asp Ala Asp Ala Val 385 390 395 ctc acc aac ctg cag acc ctg cgt atc ctc att gag gag aac agg aag 1552 Leu Thr Asn Leu Gln Thr Leu Arg Ile Leu Ile Glu Glu Asn Arg Lys 400 405 410 gtg atc gcc ccc atg ctg tcc cgc cac ggc aag ctg tgg tcc aac ttc 1600 Val Ile Ala Pro Met Leu Ser Arg His Gly Lys Leu Trp Ser Asn Phe 415 420 425 tgg ggc gcc ctg agc ccc gat gag tac tac gcc cgc tcc gag gac tac 1648 Trp Gly Ala Leu Ser Pro Asp Glu Tyr Tyr Ala Arg Ser Glu Asp Tyr 430 435 440 gtg gag ctg gtg cag cgg aag cga gtg ggt gtg tgg aat gta cca tac 1696 Val Glu Leu Val Gln Arg Lys Arg Val Gly Val Trp Asn Val Pro Tyr 445 450 455 460 atc tcc cag gcc tat gtg atc cgg ggt gat acc ctg cgg atg gag ctg 1744 Ile Ser Gln Ala Tyr Val Ile Arg Gly Asp Thr Leu Arg Met Glu Leu 465 470 475 ccc cag agg gat gtg ttc tcg ggc agt gac aca gac ccg gac atg gcc 1792 Pro Gln Arg Asp Val Phe Ser Gly Ser Asp Thr Asp Pro Asp Met Ala 480 485 490 ttc tgt aag agc ttt cga gac aag ggc atc ttc ctc cat ctg agc aat 1840 Phe Cys Lys Ser Phe Arg Asp Lys Gly Ile Phe Leu His Leu Ser Asn 495 500 505 cag cat gaa ttt ggc cgg ctc ctg gcc act tcc aga tac gac acg gag 1888 Gln His Glu Phe Gly Arg Leu Leu Ala Thr Ser Arg Tyr Asp Thr Glu 510 515 520 cac ctg cac ccc gac ctc tgg cag atc ttc gac aac ccc gtc gac tgg 1936 His Leu His Pro Asp Leu Trp Gln Ile Phe Asp Asn Pro Val Asp Trp 525 530 535 540 aag gag cag tac atc cac gag aac tac agc cgg gcc ctg gaa ggg aag 1984 Lys Glu Gln Tyr Ile His Glu Asn Tyr Ser Arg Ala Leu Glu Gly Lys 545 550 555 gaa tcg tgg agc agc cat gcc cgg acg tgt act ggt tcc cac tgc tgt 2032 Glu Ser Trp Ser Ser His Ala Arg Thr Cys Thr Gly Ser His Cys Cys 560 565 570 cag aac aaa tgt gtg atg agc tgg tgg cag aga tgg agc act acg gcc 2080 Gln Asn Lys Cys Val Met Ser Trp Trp Gln Arg Trp Ser Thr Thr Ala 575 580 585 agt ggt cag gcg gcc ggc atg agg att caa ggc tgg ctg gag gct acg 2128 Ser Gly Gln Ala Ala Gly Met Arg Ile Gln Gly Trp Leu Glu Ala Thr 590 595 600 aga atg tgc cca ccg tgg aca tcc aca tgaagcaggt ggggtacgag 2175 Arg Met Cys Pro Pro Trp Thr Ser Thr 605 610 gaccagtggc tgcagctgct gcggacgtat gtgggcccca tgaccgagag cctgtttccc 2235 ggttaccaca ccaaggcgcg ggcggtgatg aactttgtgg ttcgctaccg gccagacgag 2295 cagccgtctc tgcgggccac accacgactc atccaccttc accctcaacg ttgccctcaa 2355 ccacaagggc ctggactatg agggaggtgg ctgccgcttc ctgcgctacg actgtgtgat 2415 ctcctccccg aggaagggct gggcactcct gcaccccggc cgcctcaccc actaccacga 2475 ggggctgcca acgacctggg gcacacgcta catcatggtg tcctttgtcg acccctgaca 2535 ctcaaccact ctgccaaacc tgccctgcca ttgtgccttt ttagggggcc tggcccccgt 2595 cctgggagtt gggggatggg tctctctgtc tccccacttc ctgagttcat gttccgcgtg 2655 cctgaactga atatgtcacc ttgctcccaa gacacggccc tctcaggaag ctcccggagt 2715 ccccgcctct ctcctccgcc cacaggggtt cgtgggcaca gggcttctgg ggactccccg 2775 cgtgataaat tattaatgtt ccgcagtctc actctgaata aaggacagtt tgtaagt 2832 14 613 PRT Homo sapiens 14 Met Thr Phe Leu Gly Pro Gly Pro Arg Phe Leu Leu Leu Leu Pro Leu 1 5 10 15 Leu Leu Pro Pro Ala Ala Ser Ala Ser Asp Arg Pro Arg Gly Arg Asp 20 25 30 Pro Val Asn Pro Glu Lys Leu Leu Val Ile Thr Val Ala Thr Ala Glu 35 40 45 Thr Glu Gly Tyr Leu Arg Phe Leu Arg Ser Ala Glu Phe Phe Asn Tyr 50 55 60 Thr Val Arg Thr Leu Gly Leu Gly Glu Glu Trp Arg Gly Gly Asp Val 65 70 75 80 Ala Arg Thr Val Gly Gly Gly Gln Lys Val Arg Trp Leu Lys Lys Glu 85 90 95 Met Glu Lys Tyr Ala Asp Arg Glu Asp Met Ile Ile Met Phe Val Asp 100 105 110 Ser Tyr Asp Val Ile Leu Ala Gly Ser Pro Thr Glu Leu Leu Lys Lys 115 120 125 Phe Val Gln Ser Gly Ser Arg Leu Leu Phe Ser Ala Glu Ser Phe Cys 130 135 140 Trp Pro Glu Trp Gly Leu Ala Glu Gln Tyr Pro Glu Val Gly Thr Gly 145 150 155 160 Lys Arg Phe Leu Asn Ser Gly Gly Phe Ile Gly Phe Ala Thr Thr Ile 165 170 175 His Gln Ile Val Arg Gln Trp Lys Tyr Lys Asp Asp Asp Asp Asp Gln 180 185 190 Leu Phe Tyr Thr Arg Leu Tyr Leu Asp Pro Gly Leu Arg Glu Lys Leu 195 200 205 Ser Leu Asn Leu Asp His Lys Ser Arg Ile Phe Gln Asn Leu Asn Gly 210 215 220 Ala Leu Asp Glu Val Val Leu Lys Phe Asp Arg Asn Arg Val Arg Ile 225 230 235 240 Arg Asn Val Ala Tyr Asp Thr Leu Pro Ile Val Val His Gly Asn Gly 245 250 255 Pro Thr Lys Leu Gln Leu Asn Tyr Leu Gly Asn Tyr Val Pro Asn Gly 260 265 270 Trp Thr Pro Glu Gly Gly Cys Gly Phe Cys Asn Gln Asp Arg Arg Thr 275 280 285 Leu Pro Gly Gly Gln Pro Pro Pro Arg Val Phe Leu Ala Val Phe Val 290 295 300 Glu Gln Pro Thr Pro Phe Leu Pro Arg Phe Leu Gln Arg Leu Leu Leu 305 310 315 320 Leu Asp Tyr Pro Pro Asp Arg Val Thr Leu Phe Leu His Asn Asn Glu 325 330 335 Val Phe His Glu Pro His Ile Ala Asp Ser Trp Pro Gln Leu Gln Asp 340 345 350 His Phe Ser Ala Val Lys Leu Val Gly Pro Glu Glu Ala Leu Ser Pro 355 360 365 Gly Glu Ala Arg Asp Met Ala Met Asp Leu Cys Arg Gln Asp Pro Glu 370 375 380 Cys Glu Phe Tyr Phe Ser Leu Asp Ala Asp Ala Val Leu Thr Asn Leu 385 390 395 400 Gln Thr Leu Arg Ile Leu Ile Glu Glu Asn Arg Lys Val Ile Ala Pro 405 410 415 Met Leu Ser Arg His Gly Lys Leu Trp Ser Asn Phe Trp Gly Ala Leu 420 425 430 Ser Pro Asp Glu Tyr Tyr Ala Arg Ser Glu Asp Tyr Val Glu Leu Val 435 440 445 Gln Arg Lys Arg Val Gly Val Trp Asn Val Pro Tyr Ile Ser Gln Ala 450 455 460 Tyr Val Ile Arg Gly Asp Thr Leu Arg Met Glu Leu Pro Gln Arg Asp 465 470 475 480 Val Phe Ser Gly Ser Asp Thr Asp Pro Asp Met Ala Phe Cys Lys Ser 485 490 495 Phe Arg Asp Lys Gly Ile Phe Leu His Leu Ser Asn Gln His Glu Phe 500 505 510 Gly Arg Leu Leu Ala Thr Ser Arg Tyr Asp Thr Glu His Leu His Pro 515 520 525 Asp Leu Trp Gln Ile Phe Asp Asn Pro Val Asp Trp Lys Glu Gln Tyr 530 535 540 Ile His Glu Asn Tyr Ser Arg Ala Leu Glu Gly Lys Glu Ser Trp Ser 545 550 555 560 Ser His Ala Arg Thr Cys Thr Gly Ser His Cys Cys Gln Asn Lys Cys 565 570 575 Val Met Ser Trp Trp Gln Arg Trp Ser Thr Thr Ala Ser Gly Gln Ala 580 585 590 Ala Gly Met Arg Ile Gln Gly Trp Leu Glu Ala Thr Arg Met Cys Pro 595 600 605 Pro Trp Thr Ser Thr 610 15 3030 DNA Homo sapiens CDS (31)...(885) 15 ggatccaaag aattcggcac gagcgccgcg atg ccc gcg cgc cca gga cgc ctc 54 Met Pro Ala Arg Pro Gly Arg Leu 1 5 ctc ccg ctg ctg gcc cgg ccg gcg gcc ctg act gcg ctg ctg ctg ctg 102 Leu Pro Leu Leu Ala Arg Pro Ala Ala Leu Thr Ala Leu Leu Leu Leu 10 15 20 ctg ctg ggc cat ggc ggc ggc ggg cgc tgg ggc gcc cgg gcc cag gag 150 Leu Leu Gly His Gly Gly Gly Gly Arg Trp Gly Ala Arg Ala Gln Glu 25 30 35 40 gcg gcg gcg gcg gcg gcg gac ggg ccc ccc gcg gca gac ggc gag gac 198 Ala Ala Ala Ala Ala Ala Asp Gly Pro Pro Ala Ala Asp Gly Glu Asp 45 50 55 gga cag gac ccg cac agc aag cac ctg tac acg gcc gac atg ttc acg 246 Gly Gln Asp Pro His Ser Lys His Leu Tyr Thr Ala Asp Met Phe Thr 60 65 70 cac ggg atc cag agc gcc gcg cac ttc gtc atg ttc ttc gcg ccc tgg 294 His Gly Ile Gln Ser Ala Ala His Phe Val Met Phe Phe Ala Pro Trp 75 80 85 tgt gga cac tgc cag cgg ctg cag ccg act tgg aat gac ctg gga gac 342 Cys Gly His Cys Gln Arg Leu Gln Pro Thr Trp Asn Asp Leu Gly Asp 90 95 100 aaa tac aac agc atg gaa gat gcc aaa gtc tat gtg gct aaa gtg gac 390 Lys Tyr Asn Ser Met Glu Asp Ala Lys Val Tyr Val Ala Lys Val Asp 105 110 115 120 tgc acg gcc cac tcc gac gtg tgc tcc gcc cag ggg gtg cga gga tac 438 Cys Thr Ala His Ser Asp Val Cys Ser Ala Gln Gly Val Arg Gly Tyr 125 130 135 ccc acc tta aag ctt ttc aag cca ggc caa gaa gct gtg aag tac cag 486 Pro Thr Leu Lys Leu Phe Lys Pro Gly Gln Glu Ala Val Lys Tyr Gln 140 145 150 ggt cct cgg gac ttc cag aca ctg gaa aac tgg atg ctg cag aca ctg 534 Gly Pro Arg Asp Phe Gln Thr Leu Glu Asn Trp Met Leu Gln Thr Leu 155 160 165 aac gag gag cca gtg aca cca gaa ccg gaa gtg gaa ccg cca gtg ccc 582 Asn Glu Glu Pro Val Thr Pro Glu Pro Glu Val Glu Pro Pro Val Pro 170 175 180 ccg agc tca agc aag ggc tgt atg agc tct cag caa gca act ttg agc 630 Pro Ser Ser Ser Lys Gly Cys Met Ser Ser Gln Gln Ala Thr Leu Ser 185 190 195 200 tgc acg ttg cac aag gcg acc act tta tca agt tct tcg ctc cgt ggt 678 Cys Thr Leu His Lys Ala Thr Thr Leu Ser Ser Ser Ser Leu Arg Gly 205 210 215 gtg gtc act gca aag ccc tgg ctc caa cct ggg agc agc tgg ctc tgg 726 Val Val Thr Ala Lys Pro Trp Leu Gln Pro Gly Ser Ser Trp Leu Trp 220 225 230 gcc ttg aac att ccg aaa ctg tca aga ttg gca agg ttg att gta cac 774 Ala Leu Asn Ile Pro Lys Leu Ser Arg Leu Ala Arg Leu Ile Val His 235 240 245 agc act atg aac tct gct ccg gaa acc agg ttc gtg gct atc cca ctc 822 Ser Thr Met Asn Ser Ala Pro Glu Thr Arg Phe Val Ala Ile Pro Leu 250 255 260 ttc tct ggt tcc gag atg gga aaa agg tgg atc agt aca agg gaa agc 870 Phe Ser Gly Ser Glu Met Gly Lys Arg Trp Ile Ser Thr Arg Glu Ser 265 270 275 280 ggg att tgg agt cac tgagggagta cgtggagtcg cagctgcagc gcacagagac 925 Gly Ile Trp Ser His 285 tggagcgacg gagaccgtca cgccctcaga ggccccggtg ctggcagctg agcccgaggc 985 tgacaagggc actgtgttgg cactcactga aaataacttc gatgacacca ttgcagaagg 1045 aataaccttc atcaagtttt atgctccatg gtgtggtcat tgtaagactc tggctcctac 1105 ttgggaggaa ctctctaaaa aggaattccc tggtctggcg ggggtcaaga tcgccgaagt 1165 agactgcact gctgaacgga atatctgcag caagtattcg gtacgaggct accccacgtt 1225 attgcttttc cgaggaggga agaaagtcag tgagcacagt ggaggcagag accttgactc 1285 gttacaccgc tttgtcctga gccaagcgaa agacgaactt taggaacaca gttggaggtc 1345 acctctcctg cccagctccc gcaccctgcg tttaggagtt cagtcccaca gaggccactg 1405 ggttcccagt ggtggctgtt cagaaagcag aacatactaa gcgtgaggta tcttctttgt 1465 gtgtgtgttt tccaagccaa cacactctac agattcttta ttaagttaag tttctctaag 1525 taaatgtgta actcatggtc actgtgtaaa cattttcagt ggcgatatat cccctttgac 1585 cttctcttga tgaaatttac atggtttcct ttgagactaa aatagcattg agggaaatga 1645 aattgctgga ctatttgtgg ctcctgagtt gagtgatttt ggtgaaagaa agcacatcca 1705 aagcatagtt tacctgccca cgagttctgg aaaggtggcc ttgtggcagt attgacgttc 1765 ctctgatctt aaggtcacag ttgactcaat actgtgttgg tccgtagcat ggagcagatt 1825 gaaatgcaaa aacccacacc tctggaagat accttcacgg ccgctgctgg agcttctgtt 1885 gctgtgaata cttctctcag tgtgagaggt tagccgtgat gaaagcagcg ttacttctga 1945 ccgtgcctga gtaagagaat gctgatgcca taactttatg tgtcgatact tgtcaaatca 2005 gttactgttc aggggatcct tctgtttctc acggggtgaa acatgtcttt agttcctcat 2065 gttaacacga agccagagcc cacatgaact gttggatgtc ttccttagaa agggtaggca 2125 tggaaaattc cacgaggctc attctcagta tctcattaac tcattgaaag attccagttg 2185 tatttgtcac ctggggtgac aagaccagac aggctttccc aggcctgggt atccagggag 2245 gctctgcagc cctgctgaag ggccctaact agagttctag agtttctgat tctgtttctc 2305 agtagtcctt ttagaggctt gctatacttg gtctgcttca aggaggtcga ccttctaatg 2365 tatgaagaat gggatgcatt tgatctcaag accaaagaca gatgtcagtg ggctgctctg 2425 gccctggtgt gcacggctgt ggcagctgtt gatgccagtg tcctctaact catgctgtcc 2485 ttgtgattaa acacttctat ctcccttggg aataagcaca tacaggctta agctctaaga 2545 taggtgtttg tccttttacc atcgagctac ttcccataat aaccactttg catccaacac 2605 tcttcaccca cctcccatac gcaaggggat gtggatactt ggcccaaagt aactggtggt 2665 aggaatctta gaaacaagac cacttatact gtctgtctga ggcagaagat aacagcagca 2725 tctcgaccag cctctgcctt aaaggaaatc tttattaatc acgtgtggtt cacagataat 2785 tcttttttta aaaaaaccca acctcctaga gaagcacaac tgtcaagagt ggcttcagct 2845 ttgcatcacg agtcttgtat tccaagaaaa tcaaagtggt acaatttgtt tgtttacact 2905 atgatacttt ctaaataaac tctttttttt aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2965 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3025 aaaaa 3030 16 285 PRT Homo sapiens 16 Met Pro Ala Arg Pro Gly Arg Leu Leu Pro Leu Leu Ala Arg Pro Ala 1 5 10 15 Ala Leu Thr Ala Leu Leu Leu Leu Leu Leu Gly His Gly Gly Gly Gly 20 25 30 Arg Trp Gly Ala Arg Ala Gln Glu Ala Ala Ala Ala Ala Ala Asp Gly 35 40 45 Pro Pro Ala Ala Asp Gly Glu Asp Gly Gln Asp Pro His Ser Lys His 50 55 60 Leu Tyr Thr Ala Asp Met Phe Thr His Gly Ile Gln Ser Ala Ala His 65 70 75 80 Phe Val Met Phe Phe Ala Pro Trp Cys Gly His Cys Gln Arg Leu Gln 85 90 95 Pro Thr Trp Asn Asp Leu Gly Asp Lys Tyr Asn Ser Met Glu Asp Ala 100 105 110 Lys Val Tyr Val Ala Lys Val Asp Cys Thr Ala His Ser Asp Val Cys 115 120 125 Ser Ala Gln Gly Val Arg Gly Tyr Pro Thr Leu Lys Leu Phe Lys Pro 130 135 140 Gly Gln Glu Ala Val Lys Tyr Gln Gly Pro Arg Asp Phe Gln Thr Leu 145 150 155 160 Glu Asn Trp Met Leu Gln Thr Leu Asn Glu Glu Pro Val Thr Pro Glu 165 170 175 Pro Glu Val Glu Pro Pro Val Pro Pro Ser Ser Ser Lys Gly Cys Met 180 185 190 Ser Ser Gln Gln Ala Thr Leu Ser Cys Thr Leu His Lys Ala Thr Thr 195 200 205 Leu Ser Ser Ser Ser Leu Arg Gly Val Val Thr Ala Lys Pro Trp Leu 210 215 220 Gln Pro Gly Ser Ser Trp Leu Trp Ala Leu Asn Ile Pro Lys Leu Ser 225 230 235 240 Arg Leu Ala Arg Leu Ile Val His Ser Thr Met Asn Ser Ala Pro Glu 245 250 255 Thr Arg Phe Val Ala Ile Pro Leu Phe Ser Gly Ser Glu Met Gly Lys 260 265 270 Arg Trp Ile Ser Thr Arg Glu Ser Gly Ile Trp Ser His 275 280 285 17 2133 DNA Homo sapiens CDS (185)...(1633) 17 ggatccaaag aattcggcac gaggagctac ggttctggct gcgtcctaga ggcatccggg 60 gcagtaaaac cgctgcgatc gcggaggcgg cggccaggcc gagaggcagg ccgggcaggg 120 gtgtcggacg cagggcgctg ggccgggttt cggcttcggc cacagctttt tttctcaagg 180 tgca atg aaa gcc ttc cac act ttc tgt gtt gtc ctt ctg gtg ttt ggg 229 Met Lys Ala Phe His Thr Phe Cys Val Val Leu Leu Val Phe Gly 1 5 10 15 agt gtc tct gaa gcc aag ttt gat gat ttt gag gat gag gag gac ata 277 Ser Val Ser Glu Ala Lys Phe Asp Asp Phe Glu Asp Glu Glu Asp Ile 20 25 30 gta gag tat gat gat aat gac ttc gct gaa ttt gag gat gtc atg gaa 325 Val Glu Tyr Asp Asp Asn Asp Phe Ala Glu Phe Glu Asp Val Met Glu 35 40 45 gac tct gtt act gaa tct cct caa cgg gtc ata atc act gaa gat gat 373 Asp Ser Val Thr Glu Ser Pro Gln Arg Val Ile Ile Thr Glu Asp Asp 50 55 60 gaa gat gag acc act gtg gag ttg gaa ggg cag gat gaa aac caa gaa 421 Glu Asp Glu Thr Thr Val Glu Leu Glu Gly Gln Asp Glu Asn Gln Glu 65 70 75 gga gat ttt gaa gat gca gat acc cag gag gga gat act gag agt gaa 469 Gly Asp Phe Glu Asp Ala Asp Thr Gln Glu Gly Asp Thr Glu Ser Glu 80 85 90 95 cca tat gat gat gaa gaa ttt gaa ggt tat gaa gac aaa cca gat act 517 Pro Tyr Asp Asp Glu Glu Phe Glu Gly Tyr Glu Asp Lys Pro Asp Thr 100 105 110 tct tct agc aaa aat aaa gac cca ata acg att gtt gat gtt cct gca 565 Ser Ser Ser Lys Asn Lys Asp Pro Ile Thr Ile Val Asp Val Pro Ala 115 120 125 cac ctc cag aac agc tgg gag agt tat tat cta gaa att ttg atg gtg 613 His Leu Gln Asn Ser Trp Glu Ser Tyr Tyr Leu Glu Ile Leu Met Val 130 135 140 act ggt ctg ctt gct tat atc atg aat tac atc att ggg aag aat aaa 661 Thr Gly Leu Leu Ala Tyr Ile Met Asn Tyr Ile Ile Gly Lys Asn Lys 145 150 155 aac agt cgc ctt gca cag gcc tgg ttt aac act cat agg gag ctt ttg 709 Asn Ser Arg Leu Ala Gln Ala Trp Phe Asn Thr His Arg Glu Leu Leu 160 165 170 175 gag agc aac ttt act tta gtg ggg gat gat gga act aac aaa gaa gcc 757 Glu Ser Asn Phe Thr Leu Val Gly Asp Asp Gly Thr Asn Lys Glu Ala 180 185 190 aca agc aca gga aag ttg aac cag gag aat gag cac atc tat aac ctg 805 Thr Ser Thr Gly Lys Leu Asn Gln Glu Asn Glu His Ile Tyr Asn Leu 195 200 205 tgg tgt tct ggt cga gtg tgc tgt gag ggc atg ctt atc cag ctg agg 853 Trp Cys Ser Gly Arg Val Cys Cys Glu Gly Met Leu Ile Gln Leu Arg 210 215 220 ttc ctc aag aga caa gac tta ctg aat gtc ctg gcc cgg atg atg agg 901 Phe Leu Lys Arg Gln Asp Leu Leu Asn Val Leu Ala Arg Met Met Arg 225 230 235 cca gtg agt gat caa gtg caa ata aaa gta acc atg aat gat gaa gac 949 Pro Val Ser Asp Gln Val Gln Ile Lys Val Thr Met Asn Asp Glu Asp 240 245 250 255 atg gat acc tac gta ttt gct gtt ggc aca cgg aaa gcc ttg gtg cga 997 Met Asp Thr Tyr Val Phe Ala Val Gly Thr Arg Lys Ala Leu Val Arg 260 265 270 cta cag aaa gag atg cag gat ttg agt gag ttt tgt agt gat aaa cct 1045 Leu Gln Lys Glu Met Gln Asp Leu Ser Glu Phe Cys Ser Asp Lys Pro 275 280 285 aag tct gga gca aag tat gga ctg ccg gac tct ttg gcc atc ctg tca 1093 Lys Ser Gly Ala Lys Tyr Gly Leu Pro Asp Ser Leu Ala Ile Leu Ser 290 295 300 gag atg gga gaa gtc aca gac gga atg atg gat aca aag atg gtt cac 1141 Glu Met Gly Glu Val Thr Asp Gly Met Met Asp Thr Lys Met Val His 305 310 315 ttt ctt aca cac tat gct gac aag att gaa tct gtt cat ttt tca gac 1189 Phe Leu Thr His Tyr Ala Asp Lys Ile Glu Ser Val His Phe Ser Asp 320 325 330 335 cag ttc tct ggt cca aaa att atg caa gag gaa ggt cag cct tta aag 1237 Gln Phe Ser Gly Pro Lys Ile Met Gln Glu Glu Gly Gln Pro Leu Lys 340 345 350 cta cct gac act aag agg aca ctg ttg ttt aca ttt aat gtg cct ggc 1285 Leu Pro Asp Thr Lys Arg Thr Leu Leu Phe Thr Phe Asn Val Pro Gly 355 360 365 tca ggt aac act tac cca aag gat atg gag gca ctg cta ccc ctg atg 1333 Ser Gly Asn Thr Tyr Pro Lys Asp Met Glu Ala Leu Leu Pro Leu Met 370 375 380 aac atg gtg att tat tct att gat aaa gcc aaa aag ttc cga ctc aac 1381 Asn Met Val Ile Tyr Ser Ile Asp Lys Ala Lys Lys Phe Arg Leu Asn 385 390 395 aga gaa ggc aaa caa aaa gca gat aag aac cgt gcc cga gta gaa gag 1429 Arg Glu Gly Lys Gln Lys Ala Asp Lys Asn Arg Ala Arg Val Glu Glu 400 405 410 415 aac ttc ttg aaa ctg aca cat gtg caa aga cag gaa gca gca cag tct 1477 Asn Phe Leu Lys Leu Thr His Val Gln Arg Gln Glu Ala Ala Gln Ser 420 425 430 cgg cgg gag gag aaa aaa aga gca gag aag gag cga atc atg aat gag 1525 Arg Arg Glu Glu Lys Lys Arg Ala Glu Lys Glu Arg Ile Met Asn Glu 435 440 445 gaa gat cct gag aaa cag cgc agg ctg gag gag gct gca ttg agg cgt 1573 Glu Asp Pro Glu Lys Gln Arg Arg Leu Glu Glu Ala Ala Leu Arg Arg 450 455 460 gag caa aag aag ttg gaa aag aag caa atg aaa atg aaa caa atc aaa 1621 Glu Gln Lys Lys Leu Glu Lys Lys Gln Met Lys Met Lys Gln Ile Lys 465 470 475 gtg aaa gcc atg taaagccatc ccagagattt gagttctgat gccacctgta 1673 Val Lys Ala Met 480 agctctgaat tcacaggaaa catgaaaaac gccagtccat ttctcaacct taaatttcag 1733 acagtcttgg gcaactgaga aatccttatt tcatcatcta ctctgtttgg ggtttggggt 1793 tttacagaga ttgaagatac ctggaaaggg ctctgtttca agaatttttt tttccagata 1853 atcaaattat tttgattatt ttataaaagg aatgatctat gaaatctgtg taggttttaa 1913 atattttaaa aattataata caaatcatca gtgcttttag tacttcagtg tttaaagaaa 1973 taccatgaaa tttataggta gataaccaga ttgttgcttt ttgtttaaac caagcagttg 2033 aaatggctat aaagactgac tctaaaccaa gattctgcaa ataatgattg gaattgcaca 2093 ataaacattg cttgatgttt aaaaaaaaaa aaaaaaaaaa 2133 18 483 PRT Homo sapiens 18 Met Lys Ala Phe His Thr Phe Cys Val Val Leu Leu Val Phe Gly Ser 1 5 10 15 Val Ser Glu Ala Lys Phe Asp Asp Phe Glu Asp Glu Glu Asp Ile Val 20 25 30 Glu Tyr Asp Asp Asn Asp Phe Ala Glu Phe Glu Asp Val Met Glu Asp 35 40 45 Ser Val Thr Glu Ser Pro Gln Arg Val Ile Ile Thr Glu Asp Asp Glu 50 55 60 Asp Glu Thr Thr Val Glu Leu Glu Gly Gln Asp Glu Asn Gln Glu Gly 65 70 75 80 Asp Phe Glu Asp Ala Asp Thr Gln Glu Gly Asp Thr Glu Ser Glu Pro 85 90 95 Tyr Asp Asp Glu Glu Phe Glu Gly Tyr Glu Asp Lys Pro Asp Thr Ser 100 105 110 Ser Ser Lys Asn Lys Asp Pro Ile Thr Ile Val Asp Val Pro Ala His 115 120 125 Leu Gln Asn Ser Trp Glu Ser Tyr Tyr Leu Glu Ile Leu Met Val Thr 130 135 140 Gly Leu Leu Ala Tyr Ile Met Asn Tyr Ile Ile Gly Lys Asn Lys Asn 145 150 155 160 Ser Arg Leu Ala Gln Ala Trp Phe Asn Thr His Arg Glu Leu Leu Glu 165 170 175 Ser Asn Phe Thr Leu Val Gly Asp Asp Gly Thr Asn Lys Glu Ala Thr 180 185 190 Ser Thr Gly Lys Leu Asn Gln Glu Asn Glu His Ile Tyr Asn Leu Trp 195 200 205 Cys Ser Gly Arg Val Cys Cys Glu Gly Met Leu Ile Gln Leu Arg Phe 210 215 220 Leu Lys Arg Gln Asp Leu Leu Asn Val Leu Ala Arg Met Met Arg Pro 225 230 235 240 Val Ser Asp Gln Val Gln Ile Lys Val Thr Met Asn Asp Glu Asp Met 245 250 255 Asp Thr Tyr Val Phe Ala Val Gly Thr Arg Lys Ala Leu Val Arg Leu 260 265 270 Gln Lys Glu Met Gln Asp Leu Ser Glu Phe Cys Ser Asp Lys Pro Lys 275 280 285 Ser Gly Ala Lys Tyr Gly Leu Pro Asp Ser Leu Ala Ile Leu Ser Glu 290 295 300 Met Gly Glu Val Thr Asp Gly Met Met Asp Thr Lys Met Val His Phe 305 310 315 320 Leu Thr His Tyr Ala Asp Lys Ile Glu Ser Val His Phe Ser Asp Gln 325 330 335 Phe Ser Gly Pro Lys Ile Met Gln Glu Glu Gly Gln Pro Leu Lys Leu 340 345 350 Pro Asp Thr Lys Arg Thr Leu Leu Phe Thr Phe Asn Val Pro Gly Ser 355 360 365 Gly Asn Thr Tyr Pro Lys Asp Met Glu Ala Leu Leu Pro Leu Met Asn 370 375 380 Met Val Ile Tyr Ser Ile Asp Lys Ala Lys Lys Phe Arg Leu Asn Arg 385 390 395 400 Glu Gly Lys Gln Lys Ala Asp Lys Asn Arg Ala Arg Val Glu Glu Asn 405 410 415 Phe Leu Lys Leu Thr His Val Gln Arg Gln Glu Ala Ala Gln Ser Arg 420 425 430 Arg Glu Glu Lys Lys Arg Ala Glu Lys Glu Arg Ile Met Asn Glu Glu 435 440 445 Asp Pro Glu Lys Gln Arg Arg Leu Glu Glu Ala Ala Leu Arg Arg Glu 450 455 460 Gln Lys Lys Leu Glu Lys Lys Gln Met Lys Met Lys Gln Ile Lys Val 465 470 475 480 Lys Ala Met 19 1590 DNA Homo sapiens CDS (100)...(966) 19 ggatccaaag aattcggcac gagggtgggc tggcgagccg acgcggcggc ggaggaggct 60 gtgaggagtg tgtggaacag gacccgggac agaggaacc atg gct ccg cag aac 114 Met Ala Pro Gln Asn 1 5 ctg agc acc ttt tgc ctg ttg ctg cta tac ctc atc ggg gcg gtg att 162 Leu Ser Thr Phe Cys Leu Leu Leu Leu Tyr Leu Ile Gly Ala Val Ile 10 15 20 gcc gga cga gat ttc tat aag atc ttg ggg gtg cct cga agt gcc tct 210 Ala Gly Arg Asp Phe Tyr Lys Ile Leu Gly Val Pro Arg Ser Ala Ser 25 30 35 ata aag gat att aaa aag gcc tat agg aaa cta gcc ctg cag ctt cat 258 Ile Lys Asp Ile Lys Lys Ala Tyr Arg Lys Leu Ala Leu Gln Leu His 40 45 50 ccc gac cgg aac cct gat gat cca caa gcc cag gag aaa ttc cag gat 306 Pro Asp Arg Asn Pro Asp Asp Pro Gln Ala Gln Glu Lys Phe Gln Asp 55 60 65 ctg ggt gct gct tat gag gtt ctg tca gat agt gag aaa cgg aaa cag 354 Leu Gly Ala Ala Tyr Glu Val Leu Ser Asp Ser Glu Lys Arg Lys Gln 70 75 80 85 tac gat act tat ggt gaa gaa gga tta aaa gat ggt cat cag agc tcc 402 Tyr Asp Thr Tyr Gly Glu Glu Gly Leu Lys Asp Gly His Gln Ser Ser 90 95 100 cat gga gac att ttt tca cac ttc ttt ggg gat ttt ggt ttc atg ttt 450 His Gly Asp Ile Phe Ser His Phe Phe Gly Asp Phe Gly Phe Met Phe 105 110 115 gga gga acc cct cgt cag caa gac aga aat att cca aga gga agt gat 498 Gly Gly Thr Pro Arg Gln Gln Asp Arg Asn Ile Pro Arg Gly Ser Asp 120 125 130 att att gta gat cta gaa gtc act ttg gaa gaa gta tat gca gga aat 546 Ile Ile Val Asp Leu Glu Val Thr Leu Glu Glu Val Tyr Ala Gly Asn 135 140 145 ttt gtg gaa gta gtt aga aac aaa cct gtg gca agg cag gct cct ggc 594 Phe Val Glu Val Val Arg Asn Lys Pro Val Ala Arg Gln Ala Pro Gly 150 155 160 165 aaa cgg aag tgc aat tgt cgg caa gag atg cgg acc acc cag ctg ggc 642 Lys Arg Lys Cys Asn Cys Arg Gln Glu Met Arg Thr Thr Gln Leu Gly 170 175 180 cct ggg cgc ttc caa atg acc cag gag gtg gtc tgc gac gaa tgc cct 690 Pro Gly Arg Phe Gln Met Thr Gln Glu Val Val Cys Asp Glu Cys Pro 185 190 195 aat gtc aaa cta gtg aat gaa gaa cga acg ctg gaa gta gaa ata gag 738 Asn Val Lys Leu Val Asn Glu Glu Arg Thr Leu Glu Val Glu Ile Glu 200 205 210 cct ggg gtg aga gac ggc atg gag tac ccc ttt att gga gaa ggt gag 786 Pro Gly Val Arg Asp Gly Met Glu Tyr Pro Phe Ile Gly Glu Gly Glu 215 220 225 cct cac gtg gat ggg gag cct gga gat tta cgg ttc cga atc aaa gtt 834 Pro His Val Asp Gly Glu Pro Gly Asp Leu Arg Phe Arg Ile Lys Val 230 235 240 245 gtc aag cac cca ata ttt gaa agg aga gga gat gat ttg tac aca aat 882 Val Lys His Pro Ile Phe Glu Arg Arg Gly Asp Asp Leu Tyr Thr Asn 250 255 260 gtg aca atc tca tta gtt gag tca ctg gtt ggc ttt gag atg gat att 930 Val Thr Ile Ser Leu Val Glu Ser Leu Val Gly Phe Glu Met Asp Ile 265 270 275 act cac ttg gat ggt caa ggt aca tat ttc ccg gga taagatcacc 976 Thr His Leu Asp Gly Gln Gly Thr Tyr Phe Pro Gly 280 285 aggccaggag cgaagctatg gaagaaaggg gaagggctcc ccaactttga caacaacaat 1036 atcaagggct ctttgataat cacttttgat gtggattttc caaaagaaca gttaacagag 1096 gaagcgagag aaggtatcaa acagctactg aaacaagggt cagtgcagaa ggtatacaat 1156 ggactgcaag gatattgaga gtgaataaaa ttggactttg tttaaaataa gtgaataagc 1216 gatatttatt atctgcaagg tttttttgtg tgtgtttttg tttttatttt caatatgcaa 1276 gttaggctta atttttttat ctaatgatca tcatgaaatg aataagaggg cttaagaatt 1336 tgtccatttg cattcggaaa agaatgacca gcaaaaggtt tactaatacc tctccctttg 1396 gggatttaat gtctggtgct gccgcctgag tttcaagaat taaagctgca agaggactcc 1456 aggagcaaaa gaaacccaat atagagggtt ggagttgtta gcaatttcat tcaaaatgcc 1516 aactggagaa gtctgttttt aaatacattt tgttgttatt tttaaaaaaa aaaaaaaaaa 1576 aaaaaaaaaa aaaa 1590 20 289 PRT Homo sapiens 20 Met Ala Pro Gln Asn Leu Ser Thr Phe Cys Leu Leu Leu Leu Tyr Leu 1 5 10 15 Ile Gly Ala Val Ile Ala Gly Arg Asp Phe Tyr Lys Ile Leu Gly Val 20 25 30 Pro Arg Ser Ala Ser Ile Lys Asp Ile Lys Lys Ala Tyr Arg Lys Leu 35 40 45 Ala Leu Gln Leu His Pro Asp Arg Asn Pro Asp Asp Pro Gln Ala Gln 50 55 60 Glu Lys Phe Gln Asp Leu Gly Ala Ala Tyr Glu Val Leu Ser Asp Ser 65 70 75 80 Glu Lys Arg Lys Gln Tyr Asp Thr Tyr Gly Glu Glu Gly Leu Lys Asp 85 90 95 Gly His Gln Ser Ser His Gly Asp Ile Phe Ser His Phe Phe Gly Asp 100 105 110 Phe Gly Phe Met Phe Gly Gly Thr Pro Arg Gln Gln Asp Arg Asn Ile 115 120 125 Pro Arg Gly Ser Asp Ile Ile Val Asp Leu Glu Val Thr Leu Glu Glu 130 135 140 Val Tyr Ala Gly Asn Phe Val Glu Val Val Arg Asn Lys Pro Val Ala 145 150 155 160 Arg Gln Ala Pro Gly Lys Arg Lys Cys Asn Cys Arg Gln Glu Met Arg 165 170 175 Thr Thr Gln Leu Gly Pro Gly Arg Phe Gln Met Thr Gln Glu Val Val 180 185 190 Cys Asp Glu Cys Pro Asn Val Lys Leu Val Asn Glu Glu Arg Thr Leu 195 200 205 Glu Val Glu Ile Glu Pro Gly Val Arg Asp Gly Met Glu Tyr Pro Phe 210 215 220 Ile Gly Glu Gly Glu Pro His Val Asp Gly Glu Pro Gly Asp Leu Arg 225 230 235 240 Phe Arg Ile Lys Val Val Lys His Pro Ile Phe Glu Arg Arg Gly Asp 245 250 255 Asp Leu Tyr Thr Asn Val Thr Ile Ser Leu Val Glu Ser Leu Val Gly 260 265 270 Phe Glu Met Asp Ile Thr His Leu Asp Gly Gln Gly Thr Tyr Phe Pro 275 280 285 Gly 21 1994 DNA Homo sapiens CDS (132)...(1886) 21 gagagcagac caggcccggt ggagaattag gtgttgttgg gagctcctgc ctcccacagg 60 attccagctg cagggagcct cagggactct gggccgcacg gagttggggg cattccccag 120 agagcgtcgc c atg gtc tgc agg gag cag tta tca aag aat cag gtc aag 170 Met Val Cys Arg Glu Gln Leu Ser Lys Asn Gln Val Lys 1 5 10 tgg gtg ttt gcc ggc att acc tgt gtg tct gtg gtg gtc att gcc gca 218 Trp Val Phe Ala Gly Ile Thr Cys Val Ser Val Val Val Ile Ala Ala 15 20 25 ata gtc ctt gcc atc acc ctg cgg cgg cca ggc tgt gag ctg gag gcc 266 Ile Val Leu Ala Ile Thr Leu Arg Arg Pro Gly Cys Glu Leu Glu Ala 30 35 40 45 tgc agc cct gat gcc gac atg ctg gac tac ctg ccg agc ctg ggc cag 314 Cys Ser Pro Asp Ala Asp Met Leu Asp Tyr Leu Pro Ser Leu Gly Gln 50 55 60 atc agc cag cga gat gcc ttg gag gtc acc tgg tac cac gca gcc aac 362 Ile Ser Gln Arg Asp Ala Leu Glu Val Thr Trp Tyr His Ala Ala Asn 65 70 75 agc aac aaa gcc atg aca gct gcc ctg aac agc aac atc aca gtc ctg 410 Ser Asn Lys Ala Met Thr Ala Ala Leu Asn Ser Asn Ile Thr Val Leu 80 85 90 gag gct gac gtc aat gta gaa ggg ctc ggc aca gcc aat gag aca gga 458 Glu Ala Asp Val Asn Val Glu Gly Leu Gly Thr Ala Asn Glu Thr Gly 95 100 105 gtt ccc atc atg gca cac ccc ccc act atc tac agt gac aac aca ctg 506 Val Pro Ile Met Ala His Pro Pro Thr Ile Tyr Ser Asp Asn Thr Leu 110 115 120 125 gag cag tgg ctg gac gct gtg ctg ggc tct tcc caa aag ggc atc aaa 554 Glu Gln Trp Leu Asp Ala Val Leu Gly Ser Ser Gln Lys Gly Ile Lys 130 135 140 ctg gac ttc aag aac atc aag gca gtg ggc ccc tcc ctg gac ctc ctg 602 Leu Asp Phe Lys Asn Ile Lys Ala Val Gly Pro Ser Leu Asp Leu Leu 145 150 155 cgg cag ctg aca gag gaa ggc aaa gtc cgg cgg ccc ata tgg atc aac 650 Arg Gln Leu Thr Glu Glu Gly Lys Val Arg Arg Pro Ile Trp Ile Asn 160 165 170 gct gac atc tta aag ggc ccc aac atg ctc atc tca act gag gtc aat 698 Ala Asp Ile Leu Lys Gly Pro Asn Met Leu Ile Ser Thr Glu Val Asn 175 180 185 gcc aca cag ttc ctg gcc ctg gtc cag gag aag tat ccc aag gct acc 746 Ala Thr Gln Phe Leu Ala Leu Val Gln Glu Lys Tyr Pro Lys Ala Thr 190 195 200 205 cta tct cca ggc tgg acc acc ttc tac atg tcc acg tcc cca aac agg 794 Leu Ser Pro Gly Trp Thr Thr Phe Tyr Met Ser Thr Ser Pro Asn Arg 210 215 220 acg tac acc caa gcc atg gtg gag aag atg cac gag ctg gtg gga gga 842 Thr Tyr Thr Gln Ala Met Val Glu Lys Met His Glu Leu Val Gly Gly 225 230 235 gtg ccc cag agg gtc acc ttc cct gta cgg tct tcc atg gtg cgg gct 890 Val Pro Gln Arg Val Thr Phe Pro Val Arg Ser Ser Met Val Arg Ala 240 245 250 gcc tgg ccc cac ttc agc tgg ctg ctg agc caa tct gag agg tac agc 938 Ala Trp Pro His Phe Ser Trp Leu Leu Ser Gln Ser Glu Arg Tyr Ser 255 260 265 ctg acg ctg tgg cag gct gcc tcg gac ccc atg tcg gtg gaa gat ctg 986 Leu Thr Leu Trp Gln Ala Ala Ser Asp Pro Met Ser Val Glu Asp Leu 270 275 280 285 ctc tac gtc cgg gat aac act gct gtc cac caa gtc tac tat gac atc 1034 Leu Tyr Val Arg Asp Asn Thr Ala Val His Gln Val Tyr Tyr Asp Ile 290 295 300 ttt gag cct ctc ctg tca cag ttc aag cag ctg gcc ttg aat gcc aca 1082 Phe Glu Pro Leu Leu Ser Gln Phe Lys Gln Leu Ala Leu Asn Ala Thr 305 310 315 cgg aaa cca atg tac tac acg gga ggc agc ctg atc cct ctt ctc cag 1130 Arg Lys Pro Met Tyr Tyr Thr Gly Gly Ser Leu Ile Pro Leu Leu Gln 320 325 330 ctg cct ggg gat gac ggt ctg aat gtg gag tgg ctg gtt cct gac gtc 1178 Leu Pro Gly Asp Asp Gly Leu Asn Val Glu Trp Leu Val Pro Asp Val 335 340 345 cag ggc agc ggt aaa aca gca aca atg acc ctc cca gac aca gaa ggc 1226 Gln Gly Ser Gly Lys Thr Ala Thr Met Thr Leu Pro Asp Thr Glu Gly 350 355 360 365 atg atc ctg ctg aac act ggc ctc gag gga aca gtg gct gaa aac ccc 1274 Met Ile Leu Leu Asn Thr Gly Leu Glu Gly Thr Val Ala Glu Asn Pro 370 375 380 gtg ccc att gtt cat act cca agt ggc aac atc ctg acg ctg gag tcc 1322 Val Pro Ile Val His Thr Pro Ser Gly Asn Ile Leu Thr Leu Glu Ser 385 390 395 tgc ctg cag cag ctg gcc aca cat ccc ggg cac tgg ggc atc cat ttg 1370 Cys Leu Gln Gln Leu Ala Thr His Pro Gly His Trp Gly Ile His Leu 400 405 410 caa ata gcg gag ccc gca gcc ctc cgg cca tcc ctg gcc ttg ctg gca 1418 Gln Ile Ala Glu Pro Ala Ala Leu Arg Pro Ser Leu Ala Leu Leu Ala 415 420 425 cgc ctc tcc agc ctt ggc ctc ttg cat tgg cct gtg tgg gtt ggg gcc 1466 Arg Leu Ser Ser Leu Gly Leu Leu His Trp Pro Val Trp Val Gly Ala 430 435 440 445 aaa atc tcc cac ggg agt ttt ttg gtc ccc ggc cat gtg gct ggc aga 1514 Lys Ile Ser His Gly Ser Phe Leu Val Pro Gly His Val Ala Gly Arg 450 455 460 gag ctg ctt aca gct gtg gct gag gtc ttc ccc cac gtg act gtg gca 1562 Glu Leu Leu Thr Ala Val Ala Glu Val Phe Pro His Val Thr Val Ala 465 470 475 cca ggc tgg cct gag gag gtg ctg ggc agt ggc tac agg gaa cag ctg 1610 Pro Gly Trp Pro Glu Glu Val Leu Gly Ser Gly Tyr Arg Glu Gln Leu 480 485 490 ctc aca gat atg cta gag ttg tgc cag ggg ctc tgg caa cct gtg tcc 1658 Leu Thr Asp Met Leu Glu Leu Cys Gln Gly Leu Trp Gln Pro Val Ser 495 500 505 ttc cag atg cag gcc atg ctg ctg ggc cac agc aca gct gga gcc ata 1706 Phe Gln Met Gln Ala Met Leu Leu Gly His Ser Thr Ala Gly Ala Ile 510 515 520 525 gcc agg ctg ctg gca tcc tcc ccc cgg gcc acc gtc aca gtg gag cac 1754 Ala Arg Leu Leu Ala Ser Ser Pro Arg Ala Thr Val Thr Val Glu His 530 535 540 aac cca gct ggg ggc gac tat gcc tct gtg agg aca gca ttg ctg gca 1802 Asn Pro Ala Gly Gly Asp Tyr Ala Ser Val Arg Thr Ala Leu Leu Ala 545 550 555 gct agg gct gtg gac agg acc cga gtc tac tac agg cta ccc cag ggc 1850 Ala Arg Ala Val Asp Arg Thr Arg Val Tyr Tyr Arg Leu Pro Gln Gly 560 565 570 tac cac aag gac ttg ctg gct cat gtt ggt aga aac tgagcaccca 1896 Tyr His Lys Asp Leu Leu Ala His Val Gly Arg Asn 575 580 585 ggggtggtgg gccagcggac ctcagggcgg aggcttccca cggggaggca ggaagaaata 1956 aaggtctttg gcttacaaaa aaaaaaaaca aaaaaaaa 1994 22 585 PRT Homo sapiens 22 Met Val Cys Arg Glu Gln Leu Ser Lys Asn Gln Val Lys Trp Val Phe 1 5 10 15 Ala Gly Ile Thr Cys Val Ser Val Val Val Ile Ala Ala Ile Val Leu 20 25 30 Ala Ile Thr Leu Arg Arg Pro Gly Cys Glu Leu Glu Ala Cys Ser Pro 35 40 45 Asp Ala Asp Met Leu Asp Tyr Leu Pro Ser Leu Gly Gln Ile Ser Gln 50 55 60 Arg Asp Ala Leu Glu Val Thr Trp Tyr His Ala Ala Asn Ser Asn Lys 65 70 75 80 Ala Met Thr Ala Ala Leu Asn Ser Asn Ile Thr Val Leu Glu Ala Asp 85 90 95 Val Asn Val Glu Gly Leu Gly Thr Ala Asn Glu Thr Gly Val Pro Ile 100 105 110 Met Ala His Pro Pro Thr Ile Tyr Ser Asp Asn Thr Leu Glu Gln Trp 115 120 125 Leu Asp Ala Val Leu Gly Ser Ser Gln Lys Gly Ile Lys Leu Asp Phe 130 135 140 Lys Asn Ile Lys Ala Val Gly Pro Ser Leu Asp Leu Leu Arg Gln Leu 145 150 155 160 Thr Glu Glu Gly Lys Val Arg Arg Pro Ile Trp Ile Asn Ala Asp Ile 165 170 175 Leu Lys Gly Pro Asn Met Leu Ile Ser Thr Glu Val Asn Ala Thr Gln 180 185 190 Phe Leu Ala Leu Val Gln Glu Lys Tyr Pro Lys Ala Thr Leu Ser Pro 195 200 205 Gly Trp Thr Thr Phe Tyr Met Ser Thr Ser Pro Asn Arg Thr Tyr Thr 210 215 220 Gln Ala Met Val Glu Lys Met His Glu Leu Val Gly Gly Val Pro Gln 225 230 235 240 Arg Val Thr Phe Pro Val Arg Ser Ser Met Val Arg Ala Ala Trp Pro 245 250 255 His Phe Ser Trp Leu Leu Ser Gln Ser Glu Arg Tyr Ser Leu Thr Leu 260 265 270 Trp Gln Ala Ala Ser Asp Pro Met Ser Val Glu Asp Leu Leu Tyr Val 275 280 285 Arg Asp Asn Thr Ala Val His Gln Val Tyr Tyr Asp Ile Phe Glu Pro 290 295 300 Leu Leu Ser Gln Phe Lys Gln Leu Ala Leu Asn Ala Thr Arg Lys Pro 305 310 315 320 Met Tyr Tyr Thr Gly Gly Ser Leu Ile Pro Leu Leu Gln Leu Pro Gly 325 330 335 Asp Asp Gly Leu Asn Val Glu Trp Leu Val Pro Asp Val Gln Gly Ser 340 345 350 Gly Lys Thr Ala Thr Met Thr Leu Pro Asp Thr Glu Gly Met Ile Leu 355 360 365 Leu Asn Thr Gly Leu Glu Gly Thr Val Ala Glu Asn Pro Val Pro Ile 370 375 380 Val His Thr Pro Ser Gly Asn Ile Leu Thr Leu Glu Ser Cys Leu Gln 385 390 395 400 Gln Leu Ala Thr His Pro Gly His Trp Gly Ile His Leu Gln Ile Ala 405 410 415 Glu Pro Ala Ala Leu Arg Pro Ser Leu Ala Leu Leu Ala Arg Leu Ser 420 425 430 Ser Leu Gly Leu Leu His Trp Pro Val Trp Val Gly Ala Lys Ile Ser 435 440 445 His Gly Ser Phe Leu Val Pro Gly His Val Ala Gly Arg Glu Leu Leu 450 455 460 Thr Ala Val Ala Glu Val Phe Pro His Val Thr Val Ala Pro Gly Trp 465 470 475 480 Pro Glu Glu Val Leu Gly Ser Gly Tyr Arg Glu Gln Leu Leu Thr Asp 485 490 495 Met Leu Glu Leu Cys Gln Gly Leu Trp Gln Pro Val Ser Phe Gln Met 500 505 510 Gln Ala Met Leu Leu Gly His Ser Thr Ala Gly Ala Ile Ala Arg Leu 515 520 525 Leu Ala Ser Ser Pro Arg Ala Thr Val Thr Val Glu His Asn Pro Ala 530 535 540 Gly Gly Asp Tyr Ala Ser Val Arg Thr Ala Leu Leu Ala Ala Arg Ala 545 550 555 560 Val Asp Arg Thr Arg Val Tyr Tyr Arg Leu Pro Gln Gly Tyr His Lys 565 570 575 Asp Leu Leu Ala His Val Gly Arg Asn 580 585 23 1340 DNA Homo sapiens CDS (79)...(918) 23 ggcgcttgcg ctgagcagcc cgcgagggcg gaagtgggag ctgcgaccgc gctccctgtg 60 aggtgggcaa gcggcgaa atg gcg ccc tcc ggg agt ctt gca gtt ccc ctg 111 Met Ala Pro Ser Gly Ser Leu Ala Val Pro Leu 1 5 10 gca gtc ctg gtg ctg ttg ctt tgg ggt gct ccc tgg acg cac ggg cgg 159 Ala Val Leu Val Leu Leu Leu Trp Gly Ala Pro Trp Thr His Gly Arg 15 20 25 cgg agc aac gtt cgc gtc atc acg gac gag aac tgg aga gaa ctg ctg 207 Arg Ser Asn Val Arg Val Ile Thr Asp Glu Asn Trp Arg Glu Leu Leu 30 35 40 gaa gga gac tgg atg ata gaa ttt tat gcc ccg tgg tgc cct gct tgt 255 Glu Gly Asp Trp Met Ile Glu Phe Tyr Ala Pro Trp Cys Pro Ala Cys 45 50 55 caa aat ctt caa ccg gaa tgg gaa agt ttt gct gaa tgg gga gaa gat 303 Gln Asn Leu Gln Pro Glu Trp Glu Ser Phe Ala Glu Trp Gly Glu Asp 60 65 70 75 ctt gag gtt aat att gcg aaa gta gat gtc aca gag cag cca gga ctg 351 Leu Glu Val Asn Ile Ala Lys Val Asp Val Thr Glu Gln Pro Gly Leu 80 85 90 agt gga cgg ttt atc ata act gct ctt cct act att tat cat tgt aaa 399 Ser Gly Arg Phe Ile Ile Thr Ala Leu Pro Thr Ile Tyr His Cys Lys 95 100 105 gat ggt gaa ttt agg cgc tat ctg ggt cca agg act aag aag gac ttc 447 Asp Gly Glu Phe Arg Arg Tyr Leu Gly Pro Arg Thr Lys Lys Asp Phe 110 115 120 ata aac ttt ata agt gat aaa gag tgg aag agt att gag ccc gtt tca 495 Ile Asn Phe Ile Ser Asp Lys Glu Trp Lys Ser Ile Glu Pro Val Ser 125 130 135 tca tgg ttt ggt cca ggt tct gtt ctg atg agt agt atg tca gca ctc 543 Ser Trp Phe Gly Pro Gly Ser Val Leu Met Ser Ser Met Ser Ala Leu 140 145 150 155 ttt cag cta tct atg tgg atc agg acg tgc cat aac tac ttt att gaa 591 Phe Gln Leu Ser Met Trp Ile Arg Thr Cys His Asn Tyr Phe Ile Glu 160 165 170 gac ctt gga ttg cca gtg tgg gga tca tat act gtt ttt gct tta gca 639 Asp Leu Gly Leu Pro Val Trp Gly Ser Tyr Thr Val Phe Ala Leu Ala 175 180 185 act ctg ttt tcc gga ctg tta tta gga ctc tgt atg ata ttt gtg gca 687 Thr Leu Phe Ser Gly Leu Leu Leu Gly Leu Cys Met Ile Phe Val Ala 190 195 200 gat tgc ctt tgt cct tca aaa agg cgc aga cca cag cca tac cca tac 735 Asp Cys Leu Cys Pro Ser Lys Arg Arg Arg Pro Gln Pro Tyr Pro Tyr 205 210 215 cct tca aaa aaa tta tta tca gaa tct gca caa cct ttg aaa aaa gtg 783 Pro Ser Lys Lys Leu Leu Ser Glu Ser Ala Gln Pro Leu Lys Lys Val 220 225 230 235 gag gag gaa caa gag gcg gat gaa gaa gat gtt tca gaa gaa gaa gct 831 Glu Glu Glu Gln Glu Ala Asp Glu Glu Asp Val Ser Glu Glu Glu Ala 240 245 250 gaa agt aaa gaa gga aca aac aaa gac ttt cca cag aat gcc ata aga 879 Glu Ser Lys Glu Gly Thr Asn Lys Asp Phe Pro Gln Asn Ala Ile Arg 255 260 265 caa cgc tct ctg ggt cca tca ttg gcc aca gat aaa tcc tagttaaatt 928 Gln Arg Ser Leu Gly Pro Ser Leu Ala Thr Asp Lys Ser 270 275 280 ttatagttat cttaatatta tgattttgat aaaaacagaa gattgatcat tttgtttggt 988 ttgaagtgaa ctgtgacttt tttgaatatt gcagggttca gtctagattg tcattaaatt 1048 gaagagtcta cattcagaac ataaaagcac taggtataca agtttgaaat atgatttaag 1108 cacagtatga tggtttaaat agttctctaa tttttgaaaa atcgtgccaa gcaataagat 1168 ttatgtgtat ttgtttaata ataacctatt tcaagtctga gttttgaaaa tttacatttc 1228 ccaagtattg cattattgag gtatttaaga agattatttt agagaaaaat atttctcatt 1288 tgatataatt tttctctgtt tcactgtgaa aaaaaaaaaa aaaaaaaaaa aa 1340 24 280 PRT Homo sapiens 24 Met Ala Pro Ser Gly Ser Leu Ala Val Pro Leu Ala Val Leu Val Leu 1 5 10 15 Leu Leu Trp Gly Ala Pro Trp Thr His Gly Arg Arg Ser Asn Val Arg 20 25 30 Val Ile Thr Asp Glu Asn Trp Arg Glu Leu Leu Glu Gly Asp Trp Met 35 40 45 Ile Glu Phe Tyr Ala Pro Trp Cys Pro Ala Cys Gln Asn Leu Gln Pro 50 55 60 Glu Trp Glu Ser Phe Ala Glu Trp Gly Glu Asp Leu Glu Val Asn Ile 65 70 75 80 Ala Lys Val Asp Val Thr Glu Gln Pro Gly Leu Ser Gly Arg Phe Ile 85 90 95 Ile Thr Ala Leu Pro Thr Ile Tyr His Cys Lys Asp Gly Glu Phe Arg 100 105 110 Arg Tyr Leu Gly Pro Arg Thr Lys Lys Asp Phe Ile Asn Phe Ile Ser 115 120 125 Asp Lys Glu Trp Lys Ser Ile Glu Pro Val Ser Ser Trp Phe Gly Pro 130 135 140 Gly Ser Val Leu Met Ser Ser Met Ser Ala Leu Phe Gln Leu Ser Met 145 150 155 160 Trp Ile Arg Thr Cys His Asn Tyr Phe Ile Glu Asp Leu Gly Leu Pro 165 170 175 Val Trp Gly Ser Tyr Thr Val Phe Ala Leu Ala Thr Leu Phe Ser Gly 180 185 190 Leu Leu Leu Gly Leu Cys Met Ile Phe Val Ala Asp Cys Leu Cys Pro 195 200 205 Ser Lys Arg Arg Arg Pro Gln Pro Tyr Pro Tyr Pro Ser Lys Lys Leu 210 215 220 Leu Ser Glu Ser Ala Gln Pro Leu Lys Lys Val Glu Glu Glu Gln Glu 225 230 235 240 Ala Asp Glu Glu Asp Val Ser Glu Glu Glu Ala Glu Ser Lys Glu Gly 245 250 255 Thr Asn Lys Asp Phe Pro Gln Asn Ala Ile Arg Gln Arg Ser Leu Gly 260 265 270 Pro Ser Leu Ala Thr Asp Lys Ser 275 280 25 1011 DNA Homo sapiens CDS (128)...(985) 25 ggagacttta acatcagaaa aaggatggac ttgttgcagt tgctgtagca ttcaaagtca 60 aggtgatcat ttcaaaccaa gcatcagcaa caattaaaaa tattcacttg gtatctgtag 120 tttaata atg gac caa cat caa cat ttg aat aaa aca gca gag tca gca 169 Met Asp Gln His Gln His Leu Asn Lys Thr Ala Glu Ser Ala 1 5 10 tct tca gag aaa aag aaa aca aga cgc tgc aat gga ttc aag atg ttc 217 Ser Ser Glu Lys Lys Lys Thr Arg Arg Cys Asn Gly Phe Lys Met Phe 15 20 25 30 ttg gca gcc ctg tca ttc agc tat att gct aaa gca cta ggt gga atc 265 Leu Ala Ala Leu Ser Phe Ser Tyr Ile Ala Lys Ala Leu Gly Gly Ile 35 40 45 att atg aaa att tcc atc act caa ata gaa agg aga ttt gac ata tcc 313 Ile Met Lys Ile Ser Ile Thr Gln Ile Glu Arg Arg Phe Asp Ile Ser 50 55 60 tct tct ctt gct ggt tta att gat gta agc ttt gaa att gga aat ttg 361 Ser Ser Leu Ala Gly Leu Ile Asp Val Ser Phe Glu Ile Gly Asn Leu 65 70 75 ctt gtg att gta ttt gta agt tac ttt gga tct aaa cta cac aga ccg 409 Leu Val Ile Val Phe Val Ser Tyr Phe Gly Ser Lys Leu His Arg Pro 80 85 90 aag tta att gga att ggt tgt ctc ctt atg gga act gga agt att ttg 457 Lys Leu Ile Gly Ile Gly Cys Leu Leu Met Gly Thr Gly Ser Ile Leu 95 100 105 110 aca gct tta cca cat ttc ttc atg gga tat tat agg tat tct aaa gaa 505 Thr Ala Leu Pro His Phe Phe Met Gly Tyr Tyr Arg Tyr Ser Lys Glu 115 120 125 acc cat att aat cca tca gaa aat tca aca tca agt tta tca acc tgt 553 Thr His Ile Asn Pro Ser Glu Asn Ser Thr Ser Ser Leu Ser Thr Cys 130 135 140 tta att aat caa acc tta cca ttc aat gga aca tca cct gag ata gta 601 Leu Ile Asn Gln Thr Leu Pro Phe Asn Gly Thr Ser Pro Glu Ile Val 145 150 155 gaa aaa gat tgt gta aag gaa tct ggg tca cac atg tgg atc tat gtc 649 Glu Lys Asp Cys Val Lys Glu Ser Gly Ser His Met Trp Ile Tyr Val 160 165 170 ttc atg ggg aat atg ctt cgt ggc ata ggg gaa acc ccc ata gta cca 697 Phe Met Gly Asn Met Leu Arg Gly Ile Gly Glu Thr Pro Ile Val Pro 175 180 185 190 ttg ggg att tca tac att gat gat ttt gca aaa gaa gga cat tct tcc 745 Leu Gly Ile Ser Tyr Ile Asp Asp Phe Ala Lys Glu Gly His Ser Ser 195 200 205 ttg tat tta ggt agt ttg aat gca ata gga atg att ggt cca gtc att 793 Leu Tyr Leu Gly Ser Leu Asn Ala Ile Gly Met Ile Gly Pro Val Ile 210 215 220 ggc ttt gca ctg gga tct ctg ttt gct aaa ata tac gtg gat att gga 841 Gly Phe Ala Leu Gly Ser Leu Phe Ala Lys Ile Tyr Val Asp Ile Gly 225 230 235 tat gta gat ctg agc act atc aga ata act cct aag gac tct cgt tgg 889 Tyr Val Asp Leu Ser Thr Ile Arg Ile Thr Pro Lys Asp Ser Arg Trp 240 245 250 gtt gga gct tgg tgg ctt ggt ttc ctt gtg tct gga cta ttt tcc att 937 Val Gly Ala Trp Trp Leu Gly Phe Leu Val Ser Gly Leu Phe Ser Ile 255 260 265 270 att tct tcc ata cca ttt ttt ttc ttg ccg aaa aat cca aat aaa cca 985 Ile Ser Ser Ile Pro Phe Phe Phe Leu Pro Lys Asn Pro Asn Lys Pro 275 280 285 taaaaaaaaa aaaaaaaaaa aaaaaa 1011 26 286 PRT Homo sapiens 26 Met Asp Gln His Gln His Leu Asn Lys Thr Ala Glu Ser Ala Ser Ser 1 5 10 15 Glu Lys Lys Lys Thr Arg Arg Cys Asn Gly Phe Lys Met Phe Leu Ala 20 25 30 Ala Leu Ser Phe Ser Tyr Ile Ala Lys Ala Leu Gly Gly Ile Ile Met 35 40 45 Lys Ile Ser Ile Thr Gln Ile Glu Arg Arg Phe Asp Ile Ser Ser Ser 50 55 60 Leu Ala Gly Leu Ile Asp Val Ser Phe Glu Ile Gly Asn Leu Leu Val 65 70 75 80 Ile Val Phe Val Ser Tyr Phe Gly Ser Lys Leu His Arg Pro Lys Leu 85 90 95 Ile Gly Ile Gly Cys Leu Leu Met Gly Thr Gly Ser Ile Leu Thr Ala 100 105 110 Leu Pro His Phe Phe Met Gly Tyr Tyr Arg Tyr Ser Lys Glu Thr His 115 120 125 Ile Asn Pro Ser Glu Asn Ser Thr Ser Ser Leu Ser Thr Cys Leu Ile 130 135 140 Asn Gln Thr Leu Pro Phe Asn Gly Thr Ser Pro Glu Ile Val Glu Lys 145 150 155 160 Asp Cys Val Lys Glu Ser Gly Ser His Met Trp Ile Tyr Val Phe Met 165 170 175 Gly Asn Met Leu Arg Gly Ile Gly Glu Thr Pro Ile Val Pro Leu Gly 180 185 190 Ile Ser Tyr Ile Asp Asp Phe Ala Lys Glu Gly His Ser Ser Leu Tyr 195 200 205 Leu Gly Ser Leu Asn Ala Ile Gly Met Ile Gly Pro Val Ile Gly Phe 210 215 220 Ala Leu Gly Ser Leu Phe Ala Lys Ile Tyr Val Asp Ile Gly Tyr Val 225 230 235 240 Asp Leu Ser Thr Ile Arg Ile Thr Pro Lys Asp Ser Arg Trp Val Gly 245 250 255 Ala Trp Trp Leu Gly Phe Leu Val Ser Gly Leu Phe Ser Ile Ile Ser 260 265 270 Ser Ile Pro Phe Phe Phe Leu Pro Lys Asn Pro Asn Lys Pro 275 280 285 27 2027 DNA Homo sapiens CDS (270)...(1286) 27 gacatttcat tgtaaacgac tgggagtatc tgagcaaatt atttcttagc tgactttaga 60 gaaaacggct acctatctga ccccaaaacg acttgaggaa actgtttcca cggtcctgct 120 gcagagggga agcacagtcg tcaagaagag agtggggtca ggatcaaaac acatttagtg 180 tgacttaggg aaagaaaaca ttttccctct ttgaacctct ctggatacag tcattttgcc 240 tctacttgag gatcaactgt tcaacctca atg gcc ttt cag gac ctc ctg ggt 293 Met Ala Phe Gln Asp Leu Leu Gly 1 5 cac gct ggt gac ctg tgg aga ttc cag atc ctt cag act gtt ttt ctc 341 His Ala Gly Asp Leu Trp Arg Phe Gln Ile Leu Gln Thr Val Phe Leu 10 15 20 tca atc ttt gct gtt gct aca tac ctt cat ttt atg ctg gag aac ttc 389 Ser Ile Phe Ala Val Ala Thr Tyr Leu His Phe Met Leu Glu Asn Phe 25 30 35 40 act gca ttc ata cct ggc cat cgc tgc tgg gtc cac atc ctg gac aat 437 Thr Ala Phe Ile Pro Gly His Arg Cys Trp Val His Ile Leu Asp Asn 45 50 55 gac act gtc tct gac aat gac act ggg gcc ctc agc caa gat gca ctc 485 Asp Thr Val Ser Asp Asn Asp Thr Gly Ala Leu Ser Gln Asp Ala Leu 60 65 70 ttg aga atc tcc acc cca ctg gac tca aac atg agg cca gag aag tgt 533 Leu Arg Ile Ser Thr Pro Leu Asp Ser Asn Met Arg Pro Glu Lys Cys 75 80 85 cgt cgc ttt gtt cat cct cag tgg cag ctc ctt cac ctg aat ggg acc 581 Arg Arg Phe Val His Pro Gln Trp Gln Leu Leu His Leu Asn Gly Thr 90 95 100 ttc ccc aac aca agt gac gca gac atg gag ccc tgt gtg gat ggc tgg 629 Phe Pro Asn Thr Ser Asp Ala Asp Met Glu Pro Cys Val Asp Gly Trp 105 110 115 120 gtg tat gac aga atc tcc ttc tca tcc gcc atc gtg act gag tgg gat 677 Val Tyr Asp Arg Ile Ser Phe Ser Ser Ala Ile Val Thr Glu Trp Asp 125 130 135 ctg gta tgt gac tct caa tca ctg act tca gtg gct aaa ttt gta ttc 725 Leu Val Cys Asp Ser Gln Ser Leu Thr Ser Val Ala Lys Phe Val Phe 140 145 150 atg gct gga atg atg gtg gga ggc atc cta ggc ggt cat tta tca gac 773 Met Ala Gly Met Met Val Gly Gly Ile Leu Gly Gly His Leu Ser Asp 155 160 165 agg ttt ggg aga agg ttc gtg ctc aga tgg tgt tac ctc cag gtt gcc 821 Arg Phe Gly Arg Arg Phe Val Leu Arg Trp Cys Tyr Leu Gln Val Ala 170 175 180 att gtt ggc acc tgt gca gcc ttg gct ccc acc ttc ctc att tac tgc 869 Ile Val Gly Thr Cys Ala Ala Leu Ala Pro Thr Phe Leu Ile Tyr Cys 185 190 195 200 tta cta cgc ttc ttg tct ggg att gct gca atg agc ctc ata aca aat 917 Leu Leu Arg Phe Leu Ser Gly Ile Ala Ala Met Ser Leu Ile Thr Asn 205 210 215 act att atg tta ata gcc gag tgg gca aca cac aga ttc cag gcc atg 965 Thr Ile Met Leu Ile Ala Glu Trp Ala Thr His Arg Phe Gln Ala Met 220 225 230 gga att aca ttg gga atg tgc cct tct ggt att gca ttt atg acc ctg 1013 Gly Ile Thr Leu Gly Met Cys Pro Ser Gly Ile Ala Phe Met Thr Leu 235 240 245 gca ggc ctg gct ttt gcc att cga gac tgg cat atc ctc cag ctg gtg 1061 Ala Gly Leu Ala Phe Ala Ile Arg Asp Trp His Ile Leu Gln Leu Val 250 255 260 gtg tct gta cca tac ttt gtg atc ttt ctg acc tca agt tgg ctg cta 1109 Val Ser Val Pro Tyr Phe Val Ile Phe Leu Thr Ser Ser Trp Leu Leu 265 270 275 280 gag tct gct cgg tgg ctc att atc aac aat aaa cca gag gaa ggc tta 1157 Glu Ser Ala Arg Trp Leu Ile Ile Asn Asn Lys Pro Glu Glu Gly Leu 285 290 295 aag gaa ctt aga aaa gct gca cac agg agt gga atg aag aat gcc aga 1205 Lys Glu Leu Arg Lys Ala Ala His Arg Ser Gly Met Lys Asn Ala Arg 300 305 310 gac acc cta acc ctg gag att ttg aaa tcc acc atg aaa aaa gaa ctg 1253 Asp Thr Leu Thr Leu Glu Ile Leu Lys Ser Thr Met Lys Lys Glu Leu 315 320 325 gag gca gca caa aaa aaa aaa acc ttc tct gtg tgaaatgctc cacatgccca 1306 Glu Ala Ala Gln Lys Lys Lys Thr Phe Ser Val 330 335 acatatgtaa aaggatctcc ctcctgtcct ttacgagatt tgcaaacttt atggcctatt 1366 ttggccttaa tctccatgtc cagcatctgg ggaacaatgt tttcctgttg cagactctct 1426 ttggtgcagt catcctcctg gccaactgtg ttgcaccttg ggcactgaaa tacatgaacc 1486 gtcgagcaag ccagatgctt ctcatgttcc tactggcaat ctgccttctg gccatcatat 1546 ttgtgccaca agaaatgcag acgctgcgtg aggttttggc aacactgggc ttaggagcgt 1606 ctgctcttgc caataccctt gcttttgccc atggaaatga agtaattccc accataatca 1666 gggcaagagc tatggggatc aatgcaacct ttgctaatat agcaggagcc ctggctcccc 1726 tcatgatgat cctaagtgtg tattctccac ccctgccctg gatcatctat ggagtcttcc 1786 ccttcatctc tggctttgct ttcctcctcc ttcctgaaac caggaacaag cctctgtttg 1846 acaccatcca ggatgagaaa aatgagagaa aagaccccag agaaccaaag caagaggatc 1906 cgagagtgga agtgacgcag ttttaaggaa ttccaggagc tgactgccga tcaatgagcc 1966 agatgaaggg aacaatcagg actattccta gacactagca aaaaaaaaaa aaaaaaaaaa 2026 a 2027 28 339 PRT Homo sapiens 28 Met Ala Phe Gln Asp Leu Leu Gly His Ala Gly Asp Leu Trp Arg Phe 1 5 10 15 Gln Ile Leu Gln Thr Val Phe Leu Ser Ile Phe Ala Val Ala Thr Tyr 20 25 30 Leu His Phe Met Leu Glu Asn Phe Thr Ala Phe Ile Pro Gly His Arg 35 40 45 Cys Trp Val His Ile Leu Asp Asn Asp Thr Val Ser Asp Asn Asp Thr 50 55 60 Gly Ala Leu Ser Gln Asp Ala Leu Leu Arg Ile Ser Thr Pro Leu Asp 65 70 75 80 Ser Asn Met Arg Pro Glu Lys Cys Arg Arg Phe Val His Pro Gln Trp 85 90 95 Gln Leu Leu His Leu Asn Gly Thr Phe Pro Asn Thr Ser Asp Ala Asp 100 105 110 Met Glu Pro Cys Val Asp Gly Trp Val Tyr Asp Arg Ile Ser Phe Ser 115 120 125 Ser Ala Ile Val Thr Glu Trp Asp Leu Val Cys Asp Ser Gln Ser Leu 130 135 140 Thr Ser Val Ala Lys Phe Val Phe Met Ala Gly Met Met Val Gly Gly 145 150 155 160 Ile Leu Gly Gly His Leu Ser Asp Arg Phe Gly Arg Arg Phe Val Leu 165 170 175 Arg Trp Cys Tyr Leu Gln Val Ala Ile Val Gly Thr Cys Ala Ala Leu 180 185 190 Ala Pro Thr Phe Leu Ile Tyr Cys Leu Leu Arg Phe Leu Ser Gly Ile 195 200 205 Ala Ala Met Ser Leu Ile Thr Asn Thr Ile Met Leu Ile Ala Glu Trp 210 215 220 Ala Thr His Arg Phe Gln Ala Met Gly Ile Thr Leu Gly Met Cys Pro 225 230 235 240 Ser Gly Ile Ala Phe Met Thr Leu Ala Gly Leu Ala Phe Ala Ile Arg 245 250 255 Asp Trp His Ile Leu Gln Leu Val Val Ser Val Pro Tyr Phe Val Ile 260 265 270 Phe Leu Thr Ser Ser Trp Leu Leu Glu Ser Ala Arg Trp Leu Ile Ile 275 280 285 Asn Asn Lys Pro Glu Glu Gly Leu Lys Glu Leu Arg Lys Ala Ala His 290 295 300 Arg Ser Gly Met Lys Asn Ala Arg Asp Thr Leu Thr Leu Glu Ile Leu 305 310 315 320 Lys Ser Thr Met Lys Lys Glu Leu Glu Ala Ala Gln Lys Lys Lys Thr 325 330 335 Phe Ser Val 29 2389 DNA Homo sapiens CDS (204)...(1244) 29 gggaaacagg aagtcgccca tcctcctcgc ccggcggcag ctgtccccga gcgggaggag 60 cccgaggggg cgcgagcccc gcatgaatca ttgtagtcaa tcattttcca gttctcagcc 120 gctcagttgt gatcaaggga cacgtggttt ccgaactgcc agctcagaat aggaaaataa 180 cttgggattt tatattggaa gac atg gat ctt gct gcc aac gag atc agc att 233 Met Asp Leu Ala Ala Asn Glu Ile Ser Ile 1 5 10 tat gac aaa ctt tca gag act gtt gat ttg gtg aga cag acc ggc cat 281 Tyr Asp Lys Leu Ser Glu Thr Val Asp Leu Val Arg Gln Thr Gly His 15 20 25 cag tgt ggc atg tca gag aag gca att gaa aaa ttt atc aga cag ctg 329 Gln Cys Gly Met Ser Glu Lys Ala Ile Glu Lys Phe Ile Arg Gln Leu 30 35 40 ctg gaa aag aat gaa cct cag aga ccc ccc ccg cag tat cct ctc ctt 377 Leu Glu Lys Asn Glu Pro Gln Arg Pro Pro Pro Gln Tyr Pro Leu Leu 45 50 55 ata gtt gtg tat aag gtt ctc gca acc ttg gga tta atc ttg ctc act 425 Ile Val Val Tyr Lys Val Leu Ala Thr Leu Gly Leu Ile Leu Leu Thr 60 65 70 gcc tac ttt gtg att caa cct ttc agc cca tta gca cct gag cca gtg 473 Ala Tyr Phe Val Ile Gln Pro Phe Ser Pro Leu Ala Pro Glu Pro Val 75 80 85 90 ctt tct gga gct cac acc tgg cgc tca ctc atc cat cac att agg ctg 521 Leu Ser Gly Ala His Thr Trp Arg Ser Leu Ile His His Ile Arg Leu 95 100 105 atg tcc ttg ccc att gcc aag aag tac atg tca gaa aat aag gga gtt 569 Met Ser Leu Pro Ile Ala Lys Lys Tyr Met Ser Glu Asn Lys Gly Val 110 115 120 cct ctg cat ggg ggt gat gaa gac aga ccc ttt cca gac ttt gac ccc 617 Pro Leu His Gly Gly Asp Glu Asp Arg Pro Phe Pro Asp Phe Asp Pro 125 130 135 tgg tgg aca gac gac tgt gag cag aat gag tca gag ccc att cct gcc 665 Trp Trp Thr Asp Asp Cys Glu Gln Asn Glu Ser Glu Pro Ile Pro Ala 140 145 150 aac tgc act ggc tgt gcc cag aaa cac ctg aag gtg atg ctc ctg gaa 713 Asn Cys Thr Gly Cys Ala Gln Lys His Leu Lys Val Met Leu Leu Glu 155 160 165 170 gac gcc cca agg aaa ttt gag agg ctc cat cca ctg gtg atc aag acg 761 Asp Ala Pro Arg Lys Phe Glu Arg Leu His Pro Leu Val Ile Lys Thr 175 180 185 gga aag ccc ctg ttg gag gag gag att cag cat ttt ttg tgc cag tac 809 Gly Lys Pro Leu Leu Glu Glu Glu Ile Gln His Phe Leu Cys Gln Tyr 190 195 200 cct gag gcg aca gaa ggc ttc tct gaa ggg ttt ttc gcc aag tgg tgg 857 Pro Glu Ala Thr Glu Gly Phe Ser Glu Gly Phe Phe Ala Lys Trp Trp 205 210 215 cgc tgc ttt cct gag cgg tgg ttc cca ttt cct tat cca tgg agg aga 905 Arg Cys Phe Pro Glu Arg Trp Phe Pro Phe Pro Tyr Pro Trp Arg Arg 220 225 230 cct ctg aac aga tca caa atg tta cgt gag ctt ttt cct gtt ttc act 953 Pro Leu Asn Arg Ser Gln Met Leu Arg Glu Leu Phe Pro Val Phe Thr 235 240 245 250 cac ctg cca ttt cca aaa gat gcc tct tta aac aag tgc tcc ttt ctt 1001 His Leu Pro Phe Pro Lys Asp Ala Ser Leu Asn Lys Cys Ser Phe Leu 255 260 265 cac cca gaa cct gtt gtg ggg agt aag atg cat aag atg cct gac cta 1049 His Pro Glu Pro Val Val Gly Ser Lys Met His Lys Met Pro Asp Leu 270 275 280 ttt atc att ggc agc ggt gag gcc atg ttg cag ctc atc cct ccc ttc 1097 Phe Ile Ile Gly Ser Gly Glu Ala Met Leu Gln Leu Ile Pro Pro Phe 285 290 295 cag tgc cga aga cat tgt cag tct gtg gcc atg cca ata gag cca ggg 1145 Gln Cys Arg Arg His Cys Gln Ser Val Ala Met Pro Ile Glu Pro Gly 300 305 310 gat atc ggc tat gtc gac act acc cac tgg aag gtc tac gtt ata gcc 1193 Asp Ile Gly Tyr Val Asp Thr Thr His Trp Lys Val Tyr Val Ile Ala 315 320 325 330 aga ggg gtc cag cct ttg gtc atc tgc gat gga acc gct ttc tca gaa 1241 Arg Gly Val Gln Pro Leu Val Ile Cys Asp Gly Thr Ala Phe Ser Glu 335 340 345 ctg taggaaatag aactgtgcac aggaacagct tccagagccg aaaaccaggt 1294 Leu tgaaagggga aaaataaaaa caaaaacgat gaaactgctt tctgggggtt ggttacttag 1354 ttacctgccc tttgcatgca tgtgtgaacc agctgtgagc tgcagggcag tggccagagc 1414 ctcgccctcc tgactcttcc tgcaggtggc tcaggaagga ttcagcctgg ccacttggct 1474 aggactctgc cagcacccat ctgagactga cctcttccgg gcctttggac actatgacct 1534 tgatgctgcc cttcaggcag gaaacagggc tggtgccttt cttcacctgc atggccagct 1594 tccttccctg gcagtggaga gggcagccaa caggttctaa tgtcagagcc atcctttacc 1654 aggtgggcct gcttgtcccc gtcttgcctg ccacatcact ctactttttg gaaggccatg 1714 gctgattaaa gaagttcttg tagtttccca agcaaagtgg aatctagaaa cagtgaaaaa 1774 agttcagata actttgaatt gcattcaaga agtacacttc tttcccattg tccgtggctc 1834 ttggagtctc cgtgatgcca ggctagagtc tgattatata ataattcaaa atggtaactc 1894 ccaaggtaat gctttcttcc atttcatcag gttcttttat ccccactgca ccccctcccc 1954 ttctcccttg cctatctgga tggcttctca gaagctcggc cctagtcctc cctgccttgg 2014 cggggccaga gcccactact gctgaggcag cactgctctc gtcagctgtg ttgcctttac 2074 caagtgtctt cagagggtta tgagttagag tagctggcct ggggagaggg tgcctccctg 2134 ggtttgatct ttagggtctg actttctgca gagaagatgt tttacagatg tgtcaaagct 2194 gatgtaatgt ggttggggga ggaaatccag acccaaagtg tttgtcagct gggtgtgcaa 2254 ctgcctatgt gatcctctgt cttaaaatga tttctgtctg tgctgcgaaa caaagacaag 2314 gtgaggtgtt tttctttttt gtaataatat aaagctgtgt gtttcaaaaa aaaaaaaaaa 2374 aaaaaaaaaa aaaaa 2389 30 347 PRT Homo sapiens 30 Met Asp Leu Ala Ala Asn Glu Ile Ser Ile Tyr Asp Lys Leu Ser Glu 1 5 10 15 Thr Val Asp Leu Val Arg Gln Thr Gly His Gln Cys Gly Met Ser Glu 20 25 30 Lys Ala Ile Glu Lys Phe Ile Arg Gln Leu Leu Glu Lys Asn Glu Pro 35 40 45 Gln Arg Pro Pro Pro Gln Tyr Pro Leu Leu Ile Val Val Tyr Lys Val 50 55 60 Leu Ala Thr Leu Gly Leu Ile Leu Leu Thr Ala Tyr Phe Val Ile Gln 65 70 75 80 Pro Phe Ser Pro Leu Ala Pro Glu Pro Val Leu Ser Gly Ala His Thr 85 90 95 Trp Arg Ser Leu Ile His His Ile Arg Leu Met Ser Leu Pro Ile Ala 100 105 110 Lys Lys Tyr Met Ser Glu Asn Lys Gly Val Pro Leu His Gly Gly Asp 115 120 125 Glu Asp Arg Pro Phe Pro Asp Phe Asp Pro Trp Trp Thr Asp Asp Cys 130 135 140 Glu Gln Asn Glu Ser Glu Pro Ile Pro Ala Asn Cys Thr Gly Cys Ala 145 150 155 160 Gln Lys His Leu Lys Val Met Leu Leu Glu Asp Ala Pro Arg Lys Phe 165 170 175 Glu Arg Leu His Pro Leu Val Ile Lys Thr Gly Lys Pro Leu Leu Glu 180 185 190 Glu Glu Ile Gln His Phe Leu Cys Gln Tyr Pro Glu Ala Thr Glu Gly 195 200 205 Phe Ser Glu Gly Phe Phe Ala Lys Trp Trp Arg Cys Phe Pro Glu Arg 210 215 220 Trp Phe Pro Phe Pro Tyr Pro Trp Arg Arg Pro Leu Asn Arg Ser Gln 225 230 235 240 Met Leu Arg Glu Leu Phe Pro Val Phe Thr His Leu Pro Phe Pro Lys 245 250 255 Asp Ala Ser Leu Asn Lys Cys Ser Phe Leu His Pro Glu Pro Val Val 260 265 270 Gly Ser Lys Met His Lys Met Pro Asp Leu Phe Ile Ile Gly Ser Gly 275 280 285 Glu Ala Met Leu Gln Leu Ile Pro Pro Phe Gln Cys Arg Arg His Cys 290 295 300 Gln Ser Val Ala Met Pro Ile Glu Pro Gly Asp Ile Gly Tyr Val Asp 305 310 315 320 Thr Thr His Trp Lys Val Tyr Val Ile Ala Arg Gly Val Gln Pro Leu 325 330 335 Val Ile Cys Asp Gly Thr Ala Phe Ser Glu Leu 340 345 

1. An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of: (a) a polynucleotide encoding amino acids from about 1 to about 325 of SEQ ID NO:2; about 1 to about 435 of SEQ ID NO:4; about 1 to about 339 of SEQ ID NO:6; about 1 to about 399 of SEQ ID NO:8; about 1 to about 709 of SEQ ID NO:10; about 1 to about 240 of SEQ ID NO:12; about 1 to about 613 of SEQ ID NO:14; about 1 to about 285 of SEQ ID NO:16; about 1 to about 483 of SEQ ID NO:18; about 1 to about 289 of SEQ ID NO:20; about 1 to about 585 of SEQ ID NO:22; about 1 to about 280 of SEQ ID NO:24; about 1 to about 286 of SEQ ID NO:26; about 1 to about 340 of SEQ ID NO:28; and about 1 to about 347 of SEQ ID NO:30; (b) a polynucleotide encoding amino acids from about 2 to about 325 of SEQ ID NO:2; about 2 to about 435 of SEQ ID NO:4; about 2 to about 339 of SEQ ID NO:6; about 2 to about 399 of SEQ ID NO:8; about 2 to about 709 of SEQ ID NO:10; about 2 to about 240 of SEQ ID NO:12; about 2 to about 613 of SEQ ID NO:14; about 2 to about 285 of SEQ ID NO:16; about 2 to about 483 of SEQ ID NO:18; about 2 to about 289 of SEQ ID NO:20; about 2 to about 585 of SEQ ID NO:22; about 2 to about 280 of SEQ ID NO:24; about 2 to about 286 of SEQ ID NO:26; about 2 to about 340 of SEQ ID NO:28; and about 2 to about 347 of SEQ ID NO:30; (c) a polynucleotide encoding amino acids from about 26 to about 273 of SEQ ID NO:2; about 25 to about 435 of SEQ ID NO:4; about 26 to about 339 of SEQ ID NO:6; about 20 to about 399 of SEQ ID NO:8; about 20 to about 240 of SEQ ID NO:12; about 24 to about 613 of SEQ ID NO:14; about 25 to about 285 of SEQ ID NO:16; about 21 to about 483 of SEQ ID NO:18; about 23 to about 289 of SEQ ID NO:20; about 14 to about 585 of SEQ ID NO:22; about 21 to about 280 of SEQ ID NO:24; about 27 to about 286 of SEQ ID NO:26; about 19 to about 340 of SEQ ID NO:28; and about 55 to about 347 of SEQ ID NO:30; (d) the polynucleotide complement of the polynucleotide of (a), (b), or (c); and (e) a polynucleotide at least 90% identical to the polynucleotide of (a), (b), (c), or (d).
 2. An isolated nucleic acid molecule comprising at least 690 contiguous nucleotides from the coding region of any one of SEQ ID NO:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and
 29. 3. The isolated nucleic acid molecule of claim 2, which comprises at least 900 contiguous nucleotides from the coding region of any one of SEQ ID NO:1, 3, 5, 7, 9, 13, 17, 21, 27, and
 29. 4. The isolated nucleic acid molecule of claim 3, which comprises at least 1200 contiguous nucleotides from the coding region of any one of SEQ ID NO:3, 9, 13, 17, and
 21. 5. An isolated nucleic acid molecule comprising a polynucleotide encoding a polypeptide wherein, except for at least one conservative amino acid substitution, said polypeptide has an amino acid sequence selected from the group consisting of: (a) amino acids from about 1 to about 325 of SEQ ID NO:2; about 1 to about 435 of SEQ ID NO:4; about 1 to about 339 of SEQ ID NO:6; about 1 to about 399 of SEQ ID NO:8; about 1 to about 709 of SEQ ID NO:10; about 1 to about 240 of SEQ ID NO:12; about 1 to about 613 of SEQ ID NO:14; about 1 to about 285 of SEQ ID NO:16; about 1 to about 483 of SEQ ID NO:18; about 1 to about 289 of SEQ ID NO:20; about 1 to about 585 of SEQ ID NO:22; about 1 to about 280 of SEQ ID NO:24; about 1 to about 286 of SEQ ID NO:26; about 1 to about 340 of SEQ ID NO:28; and about 1 to about 347 of SEQ ID NO:30; (b) amino acids from about 2 to about 325 of SEQ ID NO:2; about 2 to about 435 of SEQ ID NO:4; about 2 to about 339 of SEQ ID NO:6; about 2 to about 399 of SEQ ID NO:8; about 2 to about 709 of SEQ ID NO:10; about 2 to about 240 of SEQ ID NO:12; about 2 to about 613 of SEQ ID NO:14; about 2 to about 285 of SEQ ID NO:16; about 2 to about 483 of SEQ ID NO:18; about 2 to about 289 of SEQ ID NO:20; about 2 to about 585 of SEQ ID NO:22; about 2 to about 280 of SEQ ID NO:24; about 2 to about 286 of SEQ ID NO:26; about 2 to about 340 of SEQ ID NO:28; and about 2 to about 347 of SEQ ID NO:30; and (c) amino acids from about 26 to about 273 of SEQ ID NO:2; about 25 to about 435 of SEQ ID NO:4; about 26 to about 339 of SEQ ID NO:6; about 20 to about 399 of SEQ ID NO:8; about 20 to about 240 of SEQ ID NO:12; about 24 to about 613 of SEQ ID NO:14; about 25 to about 285 of SEQ ID NO:16; about 21 to about 483 of SEQ ID NO:18; about 23 to about 289 of SEQ ID NO:20; about 14 to about 585 of SEQ ID NO:22; about 21 to about 280 of SEQ ID NO:24; about 27 to about 286 of SEQ ID NO:26; about 19 to about 340 of SEQ ID NO:28; and about 55 to about 347 of SEQ ID NO:30.
 6. The isolated nucleic acid molecule of claim 1, which is DNA.
 7. A method of making a recombinant vector comprising inserting a nucleic acid molecule of claim 1 into a vector in operable linkage to a promoter.
 8. A recombinant vector produced by the method of claim
 7. 9. A method of making a recombinant host cell comprising introducing the recombinant vector of claim 8 into a host cell.
 10. A recombinant host cell produced by the method of claim
 9. 11. A recombinant method of producing a polypeptide, comprising culturing the recombinant host cell of claim 10 under conditions such that said polypeptide is expressed and recovering said polypeptide.
 12. An isolated polypeptide comprising amino acids at least 95% identical to amino acids selected from the group consisting of: (a) amino acids from about 1 to about 325 of SEQ ID NO:2; about 1 to about 435 of SEQ ID NO:4; about 1 to about 339 of SEQ ID NO:6; about 1 to about 399 of SEQ ID NO:8; about 1 to about 709 of SEQ ID NO:10; about 1 to about 240 of SEQ ID NO:12; about 1 to about 613 of SEQ ID NO:14; about 1 to about 285 of SEQ ID NO:16; about 1 to about 483 of SEQ ID NO:18; about 1 to about 289 of SEQ ID NO:20; about 1 to about 585 of SEQ ID NO:22; about 1 to about 280 of SEQ ID NO:24; about 1 to about 286 of SEQ ID NO:26; about 1 to about 340 of SEQ ID NO:28; and about 1 to about 347 of SEQ ID NO:30; (b) amino acids from about 2 to about 325 of SEQ ID NO:2; about 2 to about 435 of SEQ ID NO:4; about 2 to about 339 of SEQ ID NO:6; about 2 to about 399 of SEQ ID NO:8; about 2 to about 709 of SEQ ID NO:10; about 2 to about 240 of SEQ ID NO:12; about 2 to about 613 of SEQ ID NO:14; about 2 to about 285 of SEQ ID NO:16; about 2 to about 483 of SEQ ID NO:18; about 2 to about 289 of SEQ ID NO:20; about 2 to about 585 of SEQ ID NO:22; about 2 to about 280 of SEQ ID NO:24; about 2 to about 286 of SEQ ID NO:26; about 2 to about 340 of SEQ ID NO:28; and about 2 to about 347 of SEQ ID NO:30; and (c) amino acids from about 26 to about 273 of SEQ ID NO:2; about 25 to about 435 of SEQ ID NO:4; about 26 to about 339 of SEQ ID NO:6; about 20 to about 399 of SEQ ID NO:8; about 20 to about 240 of SEQ ID NO:12; about 24 to about 613 of SEQ ID NO:14; about 25 to about 285 of SEQ ID NO:16; about 21 to about 483 of SEQ ID NO:18; about 23 to about 289 of SEQ ID NO:20; about 14 to about 585 of SEQ ID NO:22; about 21 to about 280 of SEQ ID NO:24; about 27 to about 286 of SEQ ID NO:26; about 19 to about 340 of SEQ ID NO:28; and about 55 to about 347 of SEQ ID NO:30.
 13. An isolated polypeptide wherein, except for at least one conservative amino acid substitution, said polypeptide has an amino acid sequence selected from the group consisting of: (a) amino acids from about 1 to about 325 of SEQ ID NO:2; about 1 to about 435 of SEQ ID NO:4; about 1 to about 339 of SEQ ID NO:6; about 1 to about 399 of SEQ ID NO:8; about 1 to about 709 of SEQ ID NO:10; about 1 to about 240 of SEQ ID NO:12; about 1 to about 613 of SEQ ID NO:14; about 1 to about 285 of SEQ ID NO:16; about 1 to about 483 of SEQ ID NO:18; about 1 to about 289 of SEQ ID NO:20; about 1 to about 585 of SEQ ID NO:22; about 1 to about 280 of SEQ ID NO:24; about 1 to about 286 of SEQ ID NO:26; about 1 to about 340 of SEQ ID NO:28; and about 1 to about 347 of SEQ ID NO:30; (b) amino acids from about 2 to about 325 of SEQ ID NO:2; about 2 to about 435 of SEQ ID NO:4; about 2 to about 339 of SEQ ID NO:6; about 2 to about 399 of SEQ ID NO:8; about 2 to about 709 of SEQ ID NO:10; about 2 to about 240 of SEQ ID NO:12; about 2 to about 613 of SEQ ID NO:14; about 2 to about 285 of SEQ ID NO:16; about 2 to about 483 of SEQ ID NO:18; about 2 to about 289 of SEQ ID NO:20; about 2 to about 585 of SEQ ID NO:22; about 2 to about 280 of SEQ ID NO:24; about 2 to about 286 of SEQ ID NO:26; about 2 to about 340 of SEQ ID NO:28; and about 2 to about 347 of SEQ ID NO:30; and (c) amino acids from about 26 to about 273 of SEQ ID NO:2; about 25 to about 435 of SEQ ID NO:4; about 26 to about 339 of SEQ ID NO:6; about 20 to about 399 of SEQ ID NO:8; about 20 to about 240 of SEQ ID NO:12; about 24 to about 613 of SEQ ID NO:14; about 25 to about 285 of SEQ ID NO:16; about 21 to about 483 of SEQ ID NO:18; about 23 to about 289 of SEQ ID NO:20; about 14 to about 585 of SEQ ID NO:22; about 21 to about 280 of SEQ ID NO:24; about 27 to about 286 of SEQ ID NO:26; about 19 to about 340 of SEQ ID NO:28; and about 55 to about 347 of SEQ ID NO:30.
 14. An isolated polypeptide comprising amino acids selected from the group consisting of: (a) amino acids from about 1 to about 325 of SEQ ID NO:2; about 1 to about 435 of SEQ ID NO:4; about 1 to about 339 of SEQ ID NO:6; about 1 to about 399 of SEQ ID NO:8; about 1 to about 709 of SEQ ID NO:10; about 1 to about 240 of SEQ ID NO:12; about 1 to about 613 of SEQ ID NO:14; about 1 to about 285 of SEQ ID NO:16; about 1 to about 483 of SEQ ID NO:18; about 1 to about 289 of SEQ ID NO:20; about 1 to about 585 of SEQ ID NO:22; about 1 to about 280 of SEQ ID NO:24; about 1 to about 286 of SEQ ID NO:26; about 1 to about 340 of SEQ ID NO:28; and about 1 to about 347 of SEQ ID NO:30; (b) amino acids from about 2 to about 325 of SEQ ID NO:2; about 2 to about 435 of SEQ ID NO:4; about 2 to about 339 of SEQ ID NO:6; about 2 to about 399 of SEQ ID NO:8; about 2 to about 709 of SEQ ID NO:10; about 2 to about 240 of SEQ ID NO:12; about 2 to about 613 of SEQ ID NO:14; about 2 to about 285 of SEQ ID NO:16; about 2 to about 483 of SEQ ID NO:18; about 2 to about 289 of SEQ ID NO:20; about 2 to about 585 of SEQ ID NO:22; about 2 to about 280 of SEQ ID NO:24; about 2 to about 286 of SEQ ID NO:26; about 2 to about 340 of SEQ ID NO:28; and about 2 to about 347 of SEQ ID NO:30; and (c) amino acids from about 26 to about 273 of SEQ ID NO:2; about 25 to about 435 of SEQ ID NO:4; about 26 to about 339 of SEQ ID NO:6; about 20 to about 399 of SEQ ID NO:8; about 20 to about 240 of SEQ ID NO:12; about 24 to about 613 of SEQ ID NO:14; about 25 to about 285 of SEQ ID NO:16; about 21 to about 483 of SEQ ID NO:18; about 23 to about 289 of SEQ ID NO:20; about 14 to about 585 of SEQ ID NO:22; about 21 to about 280 of SEQ ID NO:24; about 27 to about 286 of SEQ ID NO:26; about 19 to about 340 of SEQ ID NO:28; and about 55 to about 347 of SEQ ID NO:30.
 15. An epitope-bearing portion of the polypeptide of any one of SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and
 30. 16. The epitope-bearing portion of claim 15, which comprises about 8 to 25 contiguous amino acids of any one of SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and
 30. 17. The epitope-bearing portion of claim 15, which comprises about 10 to 15 contiguous amino acids of any one of SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, and
 30. 18. An isolated antibody that binds specifically to the polypeptide of claim
 12. 19. An isolated antibody that binds specifically to a polypeptide of claim
 13. 20. An isolated antibody that binds specifically to the polypeptide of claim
 14. 21. An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of: (a) a polynucleotide encoding amino acids from about 1 to about 13 and about 34 to about 585 of SEQ ID NO:22, wherein said amino acids about 13 and about 34 are joined by a peptide bond; (b) a polynucleotide encoding amino acids from about 1 to about 20 and about 180 to about 280 of SEQ ID NO:24, wherein said amino acids about 20 and about 180 are joined by a peptide bond; (c) a polynucleotide encoding amino acids from about 1 to about 179 of SEQ ID NO:24; (d) a polynucleotide encoding amino acids from about 21 to about 206 of SEQ ID NO:24; (e) a polynucleotide encoding amino acids from about 1 to about 26 and about 61 to about 286 of SEQ ID NO:26, wherein said amino acids about 26 and about 61 are joined by a peptide bond; (f) a polynucleotide encoding amino acids from about 27 to about 53 and about 257 to about 286 of SEQ ID NO:26, wherein said amino acids about 27 and about 257 are joined by a peptide bond; (g) a polynucleotide encoding amino acids from about 1 to about 18 and about 144 to about 340 of SEQ ID NO:28, wherein said amino acids about 18 and about 144 are joined by a peptide bond;
 22. A fusion protein comprising a first protein segment and a second protein segment fused together by means of a peptide bond, wherein the first protein segment consists of at least 8 contiguous amino acids of an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and
 30. 23. The fusion protein of claim 22 wherein the first protein segment consists of an amino acid sequence selected from the group consisting of amino acid sequence shown in SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and
 30. 